Daily Papers

Current protein language models (PLMs) learn protein representations mainly based on their sequences, thereby well capturing co-evolutionary information, but they are unable to explicitly acquire protein functions, which is the end goal of protein representation learning. Fortunately, for many proteins, their textual property descriptions are available, where their various functions are also described. Motivated by this fact, we first build the ProtDescribe dataset to augment protein sequences with text descriptions of their functions and other important properties. Based on this dataset, we propose the ProtST framework to enhance Protein Sequence pre-training and understanding by biomedical Texts. During pre-training, we design three types of tasks, i.e., unimodal mask prediction, multimodal representation alignment and multimodal mask prediction, to enhance a PLM with protein property information with different granularities and, at the same time, preserve the PLM's original representation power. On downstream tasks, ProtST enables both supervised learning and zero-shot prediction. We verify the superiority of ProtST-induced PLMs over previous ones on diverse representation learning benchmarks. Under the zero-shot setting, we show the effectiveness of ProtST on zero-shot protein classification, and ProtST also enables functional protein retrieval from a large-scale database without any function annotation.

Recent advancements in conversational large language models (LLMs), such as ChatGPT, have demonstrated remarkable promise in various domains, including drug discovery. However, existing works mainly focus on investigating the capabilities of conversational LLMs on chemical reaction and retrosynthesis. While drug editing, a critical task in the drug discovery pipeline, remains largely unexplored. To bridge this gap, we propose ChatDrug, a framework to facilitate the systematic investigation of drug editing using LLMs. ChatDrug jointly leverages a prompt module, a retrieval and domain feedback (ReDF) module, and a conversation module to streamline effective drug editing. We empirically show that ChatDrug reaches the best performance on 33 out of 39 drug editing tasks, encompassing small molecules, peptides, and proteins. We further demonstrate, through 10 case studies, that ChatDrug can successfully identify the key substructures (e.g., the molecule functional groups, peptide motifs, and protein structures) for manipulation, generating diverse and valid suggestions for drug editing. Promisingly, we also show that ChatDrug can offer insightful explanations from a domain-specific perspective, enhancing interpretability and enabling informed decision-making. This research sheds light on the potential of ChatGPT and conversational LLMs for drug editing. It paves the way for a more efficient and collaborative drug discovery pipeline, contributing to the advancement of pharmaceutical research and development.

In recent years, protein-text models have gained significant attention for their potential in protein generation and understanding. Current approaches focus on integrating protein-related knowledge into large language models through continued pretraining and multi-modal alignment, enabling simultaneous comprehension of textual descriptions and protein sequences. Through a thorough analysis of existing model architectures and text-based protein understanding benchmarks, we identify significant data leakage issues present in current benchmarks. Moreover, conventional metrics derived from natural language processing fail to accurately assess the model's performance in this domain. To address these limitations, we reorganize existing datasets and introduce a novel evaluation framework based on biological entities. Motivated by our observation, we propose a retrieval-enhanced method, which significantly outperforms fine-tuned LLMs for protein-to-text generation and shows accuracy and efficiency in training-free scenarios. Our code and data can be seen at https://github.com/IDEA-XL/RAPM.

Protein homology search underlies function annotation, structure prediction, and evolutionary analysis, but remains challenging in the "twilight zone," where global sequence similarity is weak and classical alignment methods lose sensitivity. Protein language models provide context-aware representations that could improve alignment sensitivity in this regime. However, prior protein embedding-based retrieval pipelines often pool these representations into a single vector, potentially obscuring local motifs, domains, or conserved residues that reveal remote homology. We introduce ProtoCol, a model which represents proteins as sets of residue embeddings and uses ColBERT-style late interaction to test whether residue-level comparison improves homolog retrieval. ProtoCol encodes proteins independently, keeps candidate representations pre-computable, and scores candidates with MaxSim over residue embeddings. On SCOPe superfamily and Pfam clan benchmarks, ProtoCol outperforms sequence-composition, alignment-based, pooled PLM, and trained single-vector baselines, supporting late interaction as an effective retrieval layer for remote homology search.

Protein function prediction is a crucial task in bioinformatics, with significant implications for understanding biological processes and disease mechanisms. While the relationship between sequence and function has been extensively explored, translating protein structure to function continues to present substantial challenges. Various models, particularly, CNN and graph-based deep learning approaches that integrate structural and functional data, have been proposed to address these challenges. However, these methods often fall short in elucidating the functional significance of key residues essential for protein functionality, as they predominantly adopt a retrospective perspective, leading to suboptimal performance. Inspired by region proposal networks in computer vision, we introduce the Protein Region Proposal Network (ProteinRPN) for accurate protein function prediction. Specifically, the region proposal module component of ProteinRPN identifies potential functional regions (anchors) which are refined through the hierarchy-aware node drop pooling layer favoring nodes with defined secondary structures and spatial proximity. The representations of the predicted functional nodes are enriched using attention mechanisms and subsequently fed into a Graph Multiset Transformer, which is trained with supervised contrastive (SupCon) and InfoNCE losses on perturbed protein structures. Our model demonstrates significant improvements in predicting Gene Ontology (GO) terms, effectively localizing functional residues within protein structures. The proposed framework provides a robust, scalable solution for protein function annotation, advancing the understanding of protein structure-function relationships in computational biology.

Motivation: Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein Q&A systems. To tackle these issues, we propose the Prot2Chat framework. Results: We modified ProteinMPNN to encode protein sequence and structural information in a unified way. We used a large language model (LLM) to encode questions into vectors and developed a protein-text adapter to compress protein information into virtual tokens based on these vectors, achieving the early fusion of text and protein information. Finally, the same LLM reads the virtual tokens and the questions to generate answers. To optimize training efficiency, we froze the encoder and employed Low-Rank Adaptation (LoRA) techniques for the LLM. Experiments on two datasets show that both automated metrics and expert evaluations demonstrate the superior performance of our model, and zero-shot prediction results highlight its generalization ability. The models and codes are available at https://github.com/ wangzc1233/Prot2Chat. Contact: zqcao@suda.edu.cn or wangzc025@163.com Key words: Protein Q&A, Early-Fusion, LLM

Biological literature retrieval systems are often developed and evaluated using broad biomedical corpora and general-purpose search tasks. However, many curated knowledge bases operate in narrower model-organism domains, where the literature is sparse and terminology is organism-specific. We introduce a retrieval benchmark from dictyBase for Dictyostelium, a model organism in cell and developmental biology. The benchmark consists of curator-generated biological queries linked to PubMed-indexed articles, together with structured gene annotations. Using this benchmark, we study three factors in niche biological retrieval: cross-encoder reranking, gene-aware query expansion, and abstract-only versus full-text retrieval. We report that reranking and gene-aware query expansion improve retrieval selectively: reranking is most useful when the model is well suited to biological evidence matching, whereas curated annotations help clarify compact biological queries by reducing vocabulary mismatch. Full-text chunks substantially improve retrieval when abstracts omit supporting evidence, increasing both candidate recall and top-rank performance, although these cases are harder than queries supported by abstracts. Data and code are publicly available at https://github.com/fulaibaowang/dictycite, and the benchmark dataset is additionally archived on Zenodo.

Protein language models (pLMs) produce per-residue representations that capture evolutionary and structural information, yet their mean-pooled sequence embeddings are not explicitly trained to reflect functional, evolutionary or structural similarity between proteins. We present Protein Sentence Transformers (ProtSent), a contrastive fine-tuning framework for adapting PLMs into general-purpose embedding models. ProtSent trains with MultipleNegativesRankingLoss across five protein-pair datasets: Pfam families, structurally derived hard negatives, AlphaFold DB structural pairs, and StringDB protein--protein interactions, and Deep Mutational Scanning data. We evaluate on 23~downstream tasks using frozen embeddings with a k-nearest-neighbor probe to measure embedding neighborhood quality. On ESM-2 150M, ProtSent improves 15 of 23 tasks, with gains of +105% on remote homology detection, +17% on variant effect prediction, and +19.9% Recall@1 on SCOPe-40 structural retrieval. The 35M variant improves 16 of 23 tasks with +40.5% on remote homology and +15.5% Recall@1 on SCOPe-40. Contrastive fine-tuning restructures the embedding space to better capture protein function and structure, without any task-specific supervision. We release the models, public data, and training recipe and code.

Predicting protein function from sequence is a central challenge in computational biology. While existing methods rely heavily on structured ontologies or similarity-based techniques, they often lack the flexibility to express structure-free functional descriptions and novel biological functions. In this work, we introduce Prot2Text-V2, a novel multimodal sequence-to-text model that generates free-form natural language descriptions of protein function directly from amino acid sequences. Our method combines a protein language model as a sequence encoder (ESM-3B) and a decoder-only language model (LLaMA-3.1-8B-Instruct) through a lightweight nonlinear modality projector. A key innovation is our Hybrid Sequence-level Contrastive Alignment Learning (H-SCALE), which improves cross-modal learning by matching mean- and std-pooled protein embeddings with text representations via contrastive loss. After the alignment phase, we apply instruction-based fine-tuning using LoRA on the decoder to teach the model how to generate accurate protein function descriptions conditioned on the protein sequence. We train Prot2Text-V2 on about 250K curated entries from SwissProt and evaluate it under low-homology conditions, where test sequences have low similarity with training samples. Prot2Text-V2 consistently outperforms traditional and LLM-based baselines across various metrics.

Predicting transcriptomic responses to small-molecule perturbations across cell lines is central to drug discovery, but exhaustive profiling of drug-cell combinations is infeasible. We frame molecular perturbation prediction as retrieve-and-aggregate: approximate an unmeasured drug's response in a cell line by aggregating measured responses of a small set of biologically related compounds. We propose LLM-Guided Retrieval (LGR), where a large language model (LLM) ranks candidate neighbor drugs (restricted to those profiled in the target cell line); after which a fixed mean aggregator combines their observed expression deltas to form the prediction. We evaluate on the Tahoe-100M single-cell perturbation atlas under unseen-drug, unseen-cell-line, and open-world regimes. LGR consistently improves over drug mean, ChemCPA, and chemistry-based kNN baselines, with the strongest gains for unseen cell-line generalization, where it achieves higher correlation and lower error than mean baselines. Across settings, LGR improves directional (sign) accuracy of gene regulation, indicating better recovery of biologically meaningful perturbation effects even when magnitude-based metrics are similar. These results suggest that retrieval quality, rather than predictor complexity, is a key driver of zero-shot molecular perturbation prediction, and that LLMs can provide a useful biological prior when used as constrained retrieval modules.

Deep neural networks, particularly Transformers, have been widely adopted for predicting the functional properties of proteins. In this work, we focus on exploring whether Protein Transformers can capture biological intelligence among protein sequences. To achieve our goal, we first introduce a protein function dataset, namely Protein-FN, providing over 9000 protein data with meaningful labels. Second, we devise a new Transformer architecture, namely Sequence Protein Transformers (SPT), for computationally efficient protein function predictions. Third, we develop a novel Explainable Artificial Intelligence (XAI) technique called Sequence Score, which can efficiently interpret the decision-making processes of protein models, thereby overcoming the difficulty of deciphering biological intelligence bided in Protein Transformers. Remarkably, even our smallest SPT-Tiny model, which contains only 5.4M parameters, demonstrates impressive predictive accuracy, achieving 94.3% on the Antibiotic Resistance (AR) dataset and 99.6% on the Protein-FN dataset, all accomplished by training from scratch. Besides, our Sequence Score technique helps reveal that our SPT models can discover several meaningful patterns underlying the sequence structures of protein data, with these patterns aligning closely with the domain knowledge in the biology community. We have officially released our Protein-FN dataset on Hugging Face Datasets https://huggingface.co/datasets/Protein-FN/Protein-FN. Our code is available at https://github.com/fudong03/BioIntelligence.

Protein modeling is an increasingly popular area of machine learning research. Semi-supervised learning has emerged as an important paradigm in protein modeling due to the high cost of acquiring supervised protein labels, but the current literature is fragmented when it comes to datasets and standardized evaluation techniques. To facilitate progress in this field, we introduce the Tasks Assessing Protein Embeddings (TAPE), a set of five biologically relevant semi-supervised learning tasks spread across different domains of protein biology. We curate tasks into specific training, validation, and test splits to ensure that each task tests biologically relevant generalization that transfers to real-life scenarios. We benchmark a range of approaches to semi-supervised protein representation learning, which span recent work as well as canonical sequence learning techniques. We find that self-supervised pretraining is helpful for almost all models on all tasks, more than doubling performance in some cases. Despite this increase, in several cases features learned by self-supervised pretraining still lag behind features extracted by state-of-the-art non-neural techniques. This gap in performance suggests a huge opportunity for innovative architecture design and improved modeling paradigms that better capture the signal in biological sequences. TAPE will help the machine learning community focus effort on scientifically relevant problems. Toward this end, all data and code used to run these experiments are available at https://github.com/songlab-cal/tape.

Understanding the relationships between protein sequence, structure and function is a long-standing biological challenge with manifold implications from drug design to our understanding of evolution. Recently, protein language models have emerged as the preferred method for this challenge, thanks to their ability to harness large sequence databases. Yet, their reliance on expansive sequence data and parameter sets limits their flexibility and practicality in real-world scenarios. Concurrently, the recent surge in computationally predicted protein structures unlocks new opportunities in protein representation learning. While promising, the computational burden carried by such complex data still hinders widely-adopted practical applications. To address these limitations, we introduce a novel framework that enhances protein language models by integrating protein structural data. Drawing from recent advances in graph transformers, our approach refines the self-attention mechanisms of pretrained language transformers by integrating structural information with structure extractor modules. This refined model, termed Protein Structure Transformer (PST), is further pretrained on a small protein structure database, using the same masked language modeling objective as traditional protein language models. Empirical evaluations of PST demonstrate its superior parameter efficiency relative to protein language models, despite being pretrained on a dataset comprising only 542K structures. Notably, PST consistently outperforms the state-of-the-art foundation model for protein sequences, ESM-2, setting a new benchmark in protein function prediction. Our findings underscore the potential of integrating structural information into protein language models, paving the way for more effective and efficient protein modeling Code and pretrained models are available at https://github.com/BorgwardtLab/PST.

The parallels between protein sequences and natural language in their sequential structures have inspired the application of large language models (LLMs) to protein understanding. Despite the success of LLMs in NLP, their effectiveness in comprehending protein sequences remains an open question, largely due to the absence of datasets linking protein sequences to descriptive text. Researchers have then attempted to adapt LLMs for protein understanding by integrating a protein sequence encoder with a pre-trained LLM. However, this adaptation raises a fundamental question: "Can LLMs, originally designed for NLP, effectively comprehend protein sequences as a form of language?" Current datasets fall short in addressing this question due to the lack of a direct correlation between protein sequences and corresponding text descriptions, limiting the ability to train and evaluate LLMs for protein understanding effectively. To bridge this gap, we introduce ProteinLMDataset, a dataset specifically designed for further self-supervised pretraining and supervised fine-tuning (SFT) of LLMs to enhance their capability for protein sequence comprehension. Specifically, ProteinLMDataset includes 17.46 billion tokens for pretraining and 893,000 instructions for SFT. Additionally, we present ProteinLMBench, the first benchmark dataset consisting of 944 manually verified multiple-choice questions for assessing the protein understanding capabilities of LLMs. ProteinLMBench incorporates protein-related details and sequences in multiple languages, establishing a new standard for evaluating LLMs' abilities in protein comprehension. The large language model InternLM2-7B, pretrained and fine-tuned on the ProteinLMDataset, outperforms GPT-4 on ProteinLMBench, achieving the highest accuracy score. The dataset and the benchmark are available at https://huggingface.co/datasets/tsynbio/ProteinLMBench.

The complex nature of big biological systems pushed some scientists to classify its understanding under the inconceivable missions. Different leveled challenges complicated this task, one of is the prediction of a protein's function. In recent years, significant progress has been made in this field through the development of various machine learning approaches. However, most existing methods formulate the task as a multi-classification problem, i.e assigning predefined labels to proteins. In this work, we propose a novel approach, Prot2Text, which predicts a protein function's in a free text style, moving beyond the conventional binary or categorical classifications. By combining Graph Neural Networks(GNNs) and Large Language Models(LLMs), in an encoder-decoder framework, our model effectively integrates diverse data types including proteins' sequences, structures, and textual annotations. This multimodal approach allows for a holistic representation of proteins' functions, enabling the generation of detailed and accurate descriptions. To evaluate our model, we extracted a multimodal protein dataset from SwissProt, and demonstrate empirically the effectiveness of Prot2Text. These results highlight the transformative impact of multimodal models, specifically the fusion of GNNs and LLMs, empowering researchers with powerful tools for more accurate prediction of proteins' functions. The code, the models and a demo will be publicly released.

In contrast to their remarkable performance on general knowledge QA, the true abilities of Large Language Models (LLMs) in tasks demanding deep, specialized reasoning, such as in protein biology, have yet to be thoroughly investigated. Current benchmarks suffer from critical deficiencies, such as data contamination due to outdated test sets, insufficient focus on essential protein-specific tasks, and a neglect of multimodal assessments. To resolve these issues, we introduce LiveProteinBench, a contamination-free, multimodal benchmark of 12 tasks for evaluating LLM performance on protein property and function prediction. Its central innovation lies in a test set composed exclusively of proteins validated after the start of 2025, guaranteeing that the data is novel to all tested models. We benchmarked a suite of prominent general-purpose LLMs and specialized biological LLMs using both unimodal and multimodal input schemes. Our results show that: 1) General-purpose proprietary large models demonstrate superior zero-shot performance when encountering new protein data, outperforming their open-source and domain-specific counterparts by over 20\% accuracy. 2) The effective use of multi-view structural information remains a significant challenge, as the inclusion of structural images often fails to provide a consistent benefit and can even degrade performance. This highlights the limitations of current models in effectively fusing information across different modalities. 3) Models' performance scales more directly with the computational cost during inference than with its parameter count, underscoring the critical role of Chain-of-Thought reasoning capabilities for protein-specific tasks. LiveProteinBench delineates the current performance frontiers for LLMs in bioinformatics and presents new challenges for the development of future multimodal foundation models for biology

Developing effective biomedical retrieval models is important for excelling at knowledge-intensive biomedical tasks but still challenging due to the deficiency of sufficient publicly annotated biomedical data and computational resources. We present BMRetriever, a series of dense retrievers for enhancing biomedical retrieval via unsupervised pre-training on large biomedical corpora, followed by instruction fine-tuning on a combination of labeled datasets and synthetic pairs. Experiments on 5 biomedical tasks across 11 datasets verify BMRetriever's efficacy on various biomedical applications. BMRetriever also exhibits strong parameter efficiency, with the 410M variant outperforming baselines up to 11.7 times larger, and the 2B variant matching the performance of models with over 5B parameters. The training data and model checkpoints are released at https://huggingface.co/BMRetriever to ensure transparency, reproducibility, and application to new domains.

Protein function is driven by cohesive substructures, such as catalytic triads, binding pockets, and structural motifs, that occupy only a small fraction of a protein's residues. Yet existing pipelines built on protein encoders do not model proteins at the substructure level, leaving the central biological question unanswered: which substructure of a protein is responsible for its function? We introduce BioBlobs, an encoder-agnostic, end-to-end differentiable framework that compresses a protein into a small set of cohesive substructures (blobs) and predicts function from these blobs alone, so that each blob corresponds to a candidate functional region. Across diverse protein function prediction tasks and multiple sequence- and structure-based encoders, BioBlobs matches or exceeds strong baselines while operating on only a small fraction of residues. The discovered blobs adapt their spatial scale to the task, ranging from local catalytic sites to entire structural domains. Trained only on protein-level labels, BioBlobs recovers experimentally annotated catalytic sites in the M-CSA database, demonstrating unsupervised functional substructure discovery and opening a path to large-scale functional site discovery across the unannotated proteome.

Enzymes are important proteins that catalyze chemical reactions. In recent years, machine learning methods have emerged to predict enzyme function from sequence; however, there are no standardized benchmarks to evaluate these methods. We introduce CARE, a benchmark and dataset suite for the Classification And Retrieval of Enzymes (CARE). CARE centers on two tasks: (1) classification of a protein sequence by its enzyme commission (EC) number and (2) retrieval of an EC number given a chemical reaction. For each task, we design train-test splits to evaluate different kinds of out-of-distribution generalization that are relevant to real use cases. For the classification task, we provide baselines for state-of-the-art methods. Because the retrieval task has not been previously formalized, we propose a method called Contrastive Reaction-EnzymE Pretraining (CREEP) as one of the first baselines for this task and compare it to the recent method, CLIPZyme. CARE is available at https://github.com/jsunn-y/CARE/.

Generative protein language models are a natural way to design new proteins with desired functions. However, current models are either difficult to direct to produce a protein from a specific family of interest, or must be trained on a large multiple sequence alignment (MSA) from the specific family of interest, making them unable to benefit from transfer learning across families. To address this, we propose Protein Evolutionary Transformer (PoET), an autoregressive generative model of whole protein families that learns to generate sets of related proteins as sequences-of-sequences across tens of millions of natural protein sequence clusters. PoET can be used as a retrieval-augmented language model to generate and score arbitrary modifications conditioned on any protein family of interest, and can extrapolate from short context lengths to generalize well even for small families. This is enabled by a unique Transformer layer; we model tokens sequentially within sequences while attending between sequences order invariantly, allowing PoET to scale to context lengths beyond those used during training. In extensive experiments on deep mutational scanning datasets, we show that PoET outperforms existing protein language models and evolutionary sequence models for variant function prediction across proteins of all MSA depths. We also demonstrate PoET's ability to controllably generate new protein sequences.

Proteins are essential to life's processes, underpinning evolution and diversity. Advances in sequencing technology have revealed millions of proteins, underscoring the need for sophisticated pre-trained protein models for biological analysis and AI development. Facebook's ESM2, the most advanced protein language model to date, leverages a masked prediction task for unsupervised learning, crafting amino acid representations with notable biochemical accuracy. Yet, it lacks in delivering functional protein insights, signaling an opportunity for enhancing representation quality.Our study addresses this gap by incorporating protein family classification into ESM2's training.This approach, augmented with Community Propagation-Based Clustering Algorithm, improves global protein representations, while a contextual prediction task fine-tunes local amino acid accuracy. Significantly, our model achieved state-of-the-art results in several downstream experiments, demonstrating the power of combining global and local methodologies to substantially boost protein representation quality.

Elucidating the functional effect of missense variants is of crucial importance, yet challenging. To understand the impact of such variants, we fine-tuned the ESM2 protein language model to classify 20 protein features at amino acid resolution. We used the resulting models to: 1) identify protein features that are enriched in either pathogenic or benign missense variants, 2) compare the characteristics of proteins with reference or alternate alleles to understand how missense variants affect protein functionality. We show that our model can be used to reclassify some variants of unknown significance. We also demonstrate the usage of our models for understanding the potential effect of variants on protein features.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein functions. Recent sequence representation learning methods based on Protein Language Models (PLMs) excel in sequence-based tasks, but their direct adaptation to tasks involving protein structures remains a challenge. In contrast, structure-based methods leverage 3D structural information with graph neural networks and geometric pre-training methods show potential in function prediction tasks, but still suffers from the limited number of available structures. To bridge this gap, our study undertakes a comprehensive exploration of joint protein representation learning by integrating a state-of-the-art PLM (ESM-2) with distinct structure encoders (GVP, GearNet, CDConv). We introduce three representation fusion strategies and explore different pre-training techniques. Our method achieves significant improvements over existing sequence- and structure-based methods, setting new state-of-the-art for function annotation. This study underscores several important design choices for fusing protein sequence and structure information. Our implementation is available at https://github.com/DeepGraphLearning/ESM-GearNet.

We present BioMatrix, the first multimodal foundation model that natively integrates sequences, structures, and natural language for both molecules and proteins within a single decoder-only architecture. Existing biological foundation models pursue native multimodality and broad entity coverage separately: those that fuse multiple modalities under a shared objective remain confined to a single entity type, while those spanning multiple entity types either omit explicit structural modeling or rely on adapter-based designs in which the model cannot natively generate the very modalities it can read. BioMatrix closes this gap by mapping molecular sequences (supporting both SMILES and SELFIES notations), molecular structures, protein sequences, protein structures, and natural language into a shared discrete token space through a unified tokenization scheme, so that all modalities are consumed and produced uniformly under a single next-token prediction objective -- without external encoders, projection adapters, or modality-specific output heads. Built upon the Qwen3 language model (1.7B and 4B), BioMatrix is continually pretrained on 304.4 billion tokens spanning general and domain-specific text, sequence and structure views of molecules and proteins, and cross-modal corpora that interleave biomolecular entities with scientific text and link distinct entities through molecule-protein and protein-protein interaction data. After tuning on a comprehensive suite of downstream applications covering 80 tasks across 6 categories -- encompassing single-entity and multi-entity understanding and generation tasks across and within modalities -- BioMatrix achieves state-of-the-art or competitive performance on 77 out of 80 tasks, demonstrating that a single, natively multimodal generalist model can effectively match or surpass specialized approaches across a wide range of biological tasks.

Recent AI advances have enabled multi-modal systems to model and translate diverse information spaces. Extending beyond text and vision, we introduce OneProt, a multi-modal AI for proteins that integrates structural, sequence, alignment, and binding site data. Using the ImageBind framework, OneProt aligns the latent spaces of modality encoders along protein sequences. It demonstrates strong performance in retrieval tasks and surpasses state-of-the-art methods in various downstream tasks, including metal ion binding classification, gene-ontology annotation, and enzyme function prediction. This work expands multi-modal capabilities in protein models, paving the way for applications in drug discovery, biocatalytic reaction planning, and protein engineering.

Recently, there has been great interest in learning how to best represent proteins, specifically with fixed-length embeddings. Deep learning has become a popular tool for protein representation learning as a model's hidden layers produce potentially useful vector embeddings. TAPE introduced a number of benchmark tasks and showed that semi-supervised learning, via pretraining language models on a large protein corpus, improved performance on downstream tasks. Two of the tasks (fluorescence prediction and stability prediction) involve learning fitness landscapes. In this paper, we show that CNN models trained solely using supervised learning both compete with and sometimes outperform the best models from TAPE that leverage expensive pretraining on large protein datasets. These CNN models are sufficiently simple and small that they can be trained using a Google Colab notebook. We also find for the fluorescence task that linear regression outperforms our models and the TAPE models. The benchmarking tasks proposed by TAPE are excellent measures of a model's ability to predict protein function and should be used going forward. However, we believe it is important to add baselines from simple models to put the performance of the semi-supervised models that have been reported so far into perspective.

Pre-trained LLMs have demonstrated substantial capabilities across a range of conventional natural language processing (NLP) tasks, such as summarization and entity recognition. In this paper, we explore the application of LLMs in the generation of high-quality protein sequences. Specifically, we adopt a suite of pre-trained LLMs, including Mistral-7B1, Llama-2-7B2, Llama-3-8B3, and gemma-7B4, to produce valid protein sequences. All of these models are publicly available.5 Unlike previous work in this field, our approach utilizes a relatively small dataset comprising 42,000 distinct human protein sequences. We retrain these models to process protein-related data, ensuring the generation of biologically feasible protein structures. Our findings demonstrate that even with limited data, the adapted models exhibit efficiency comparable to established protein-focused models such as ProGen varieties, ProtGPT2, and ProLLaMA, which were trained on millions of protein sequences. To validate and quantify the performance of our models, we conduct comparative analyses employing standard metrics such as pLDDT, RMSD, TM-score, and REU. Furthermore, we commit to making the trained versions of all four models publicly available, fostering greater transparency and collaboration in the field of computational biology.

Protein inverse folding, the design of an amino acid sequence based on a target 3D structure, is a fundamental problem of computational protein engineering. Existing methods either generate sequences without leveraging external knowledge or relying on protein language models (PLMs). The former omits the evolutionary information stored in protein databases, while the latter is parameter-inefficient and inflexible to adapt to ever-growing protein data. To overcome the above drawbacks, in this paper we propose a novel method, called retrieval-augmented denoising diffusion (RadDiff), for protein inverse folding. Given the target protein backbone, RadDiff uses a hierarchical search strategy to efficiently retrieve structurally similar proteins from large protein databases. The retrieved structures are then aligned residue-by-residue to the target to construct a position-specific amino acid profile, which serves as an evolutionary-informed prior that conditions the denoising process. A lightweight integration module is further designed to incorporate this prior effectively. Experimental results on the CATH, PDB, and TS50 datasets show that RadDiff consistently outperforms existing methods, improving sequence recovery rate by up to 19%. Experimental results also demonstrate that RadDiff generates highly foldable sequences and scales effectively with database size.

Many proteins useful in modern medicine or bioengineering are challenging to make in the lab, fuse with other proteins in cells, or deliver to tissues in the body, because their sequences are too long. Shortening these sequences typically involves costly, time-consuming experimental campaigns. Ideally, we could instead use modern models of massive databases of sequences from nature to learn how to propose shrunken proteins that resemble sequences found in nature. Unfortunately, these models struggle to efficiently search the combinatorial space of all deletions, and are not trained with inductive biases to learn how to delete. To address this gap, we propose SCISOR, a novel discrete diffusion model that deletes letters from sequences to generate protein samples that resemble those found in nature. To do so, SCISOR trains a de-noiser to reverse a forward noising process that adds random insertions to natural sequences. As a generative model, SCISOR fits evolutionary sequence data competitively with previous large models. In evaluation, SCISOR achieves state-of-the-art predictions of the functional effects of deletions on ProteinGym. Finally, we use the SCISOR de-noiser to shrink long protein sequences, and show that its suggested deletions result in significantly more realistic proteins and more often preserve functional motifs than previous models of evolutionary sequences.

Protein language models have shown remarkable success in learning biological information from protein sequences. However, most existing models are limited by either autoencoding or autoregressive pre-training objectives, which makes them struggle to handle protein understanding and generation tasks concurrently. We propose a unified protein language model, xTrimoPGLM, to address these two types of tasks simultaneously through an innovative pre-training framework. Our key technical contribution is an exploration of the compatibility and the potential for joint optimization of the two types of objectives, which has led to a strategy for training xTrimoPGLM at an unprecedented scale of 100 billion parameters and 1 trillion training tokens. Our extensive experiments reveal that 1) xTrimoPGLM significantly outperforms other advanced baselines in 18 protein understanding benchmarks across four categories. The model also facilitates an atomic-resolution view of protein structures, leading to an advanced 3D structural prediction model that surpasses existing language model-based tools. 2) xTrimoPGLM not only can generate de novo protein sequences following the principles of natural ones, but also can perform programmable generation after supervised fine-tuning (SFT) on curated sequences. These results highlight the substantial capability and versatility of xTrimoPGLM in understanding and generating protein sequences, contributing to the evolving landscape of foundation models in protein science.

The goal of protein representation learning is to extract knowledge from protein databases that can be applied to various protein-related downstream tasks. Although protein sequence, structure, and function are the three key modalities for a comprehensive understanding of proteins, existing methods for protein representation learning have utilized only one or two of these modalities due to the difficulty of capturing the asymmetric interrelationships between them. To account for this asymmetry, we introduce our novel asymmetric multi-modal masked autoencoder (AMMA). AMMA adopts (1) a unified multi-modal encoder to integrate all three modalities into a unified representation space and (2) asymmetric decoders to ensure that sequence latent features reflect structural and functional information. The experiments demonstrate that the proposed AMMA is highly effective in learning protein representations that exhibit well-aligned inter-modal relationships, which in turn makes it effective for various downstream protein-related tasks.

We present **vstash**, a local-first document memory system that combines vector similarity search with full-text keyword matching via Reciprocal Rank Fusion (RRF) and adaptive per-query IDF weighting. All data resides in a single SQLite file using sqlite-vec for approximate nearest neighbor search and FTS5 for keyword matching. We make four primary contributions. **(1)** Self-supervised embedding refinement via hybrid retrieval disagreement: across 753 BEIR queries on SciFact, NFCorpus, and FiQA, 74.5% produce top-10 disagreement between vector-heavy (vec=0.95, fts=0.05) and FTS-heavy (vec=0.05, fts=0.95) search (per-dataset rates 63.4% / 73.4% / 86.7%, Section 5.2), providing a free training signal without human labels. Fine-tuning BGE-small (33M params) with MultipleNegativesRankingLoss on 76K disagreement triples improves NDCG@10 on all 5 BEIR datasets (up to +19.5% on NFCorpus vs. BGE-small base RRF, Table 6). On 3 of 5 datasets, under different preprocessing, the tuned 33M-parameter pipeline matches or exceeds published ColBERTv2 results (110M params) and an untrained BGE-base (110M); on FiQA and ArguAna it underperforms ColBERTv2 (Section 5.5). **(2)** Adaptive RRF with per-query IDF weighting improves NDCG@10 on all 5 BEIR datasets versus fixed weights (up to +21.4% on ArguAna), achieving 0.7263 on SciFact with BGE-small. **(3)** A negative result on post-RRF scoring: frequency+decay, history-augmented recall, and cross-encoder reranking all failed to improve NDCG. **(4)** A production-grade substrate with integrity checking, schema versioning, ranking diagnostics, and a distance-based relevance signal validated on 50,425 relevance-judged queries across the 5 BEIR datasets. Search latency remains 20.9 ms median at 50K chunks with stable NDCG. The fine-tuned model is published as `Stffens/bge-small-rrf-v2` on HuggingFace. All code, data, and experiments are open-source.

Recent years have witnessed a surge in the development of protein foundation models, significantly improving performance in protein prediction and generative tasks ranging from 3D structure prediction and protein design to conformational dynamics. However, the capabilities and limitations associated with these models remain poorly understood due to the absence of a unified evaluation framework. To fill this gap, we introduce ProteinBench, a holistic evaluation framework designed to enhance the transparency of protein foundation models. Our approach consists of three key components: (i) A taxonomic classification of tasks that broadly encompass the main challenges in the protein domain, based on the relationships between different protein modalities; (ii) A multi-metric evaluation approach that assesses performance across four key dimensions: quality, novelty, diversity, and robustness; and (iii) In-depth analyses from various user objectives, providing a holistic view of model performance. Our comprehensive evaluation of protein foundation models reveals several key findings that shed light on their current capabilities and limitations. To promote transparency and facilitate further research, we release the evaluation dataset, code, and a public leaderboard publicly for further analysis and a general modular toolkit. We intend for ProteinBench to be a living benchmark for establishing a standardized, in-depth evaluation framework for protein foundation models, driving their development and application while fostering collaboration within the field.

We are now witnessing significant progress of deep learning methods in a variety of tasks (or datasets) of proteins. However, there is a lack of a standard benchmark to evaluate the performance of different methods, which hinders the progress of deep learning in this field. In this paper, we propose such a benchmark called PEER, a comprehensive and multi-task benchmark for Protein sEquence undERstanding. PEER provides a set of diverse protein understanding tasks including protein function prediction, protein localization prediction, protein structure prediction, protein-protein interaction prediction, and protein-ligand interaction prediction. We evaluate different types of sequence-based methods for each task including traditional feature engineering approaches, different sequence encoding methods as well as large-scale pre-trained protein language models. In addition, we also investigate the performance of these methods under the multi-task learning setting. Experimental results show that large-scale pre-trained protein language models achieve the best performance for most individual tasks, and jointly training multiple tasks further boosts the performance. The datasets and source codes of this benchmark are all available at https://github.com/DeepGraphLearning/PEER_Benchmark

We present our submission to the Task 5 of SemEval-2025 that aims to aid librarians in assigning subject tags to the library records by producing a list of likely relevant tags for a given document. We frame the task as an information retrieval problem, where the document content is used to retrieve subject tags from a large subject taxonomy. We leverage two types of encoder models to build a two-stage information retrieval system -- a bi-encoder for coarse-grained candidate extraction at the first stage, and a cross-encoder for fine-grained re-ranking at the second stage. This approach proved effective, demonstrating significant improvements in recall compared to single-stage methods and showing competitive results according to qualitative evaluation.

Deep learning models have driven significant progress in predicting protein function and interactions at the protein level. While these advancements have been invaluable for many biological applications such as enzyme engineering and function annotation, a more detailed perspective is essential for understanding protein functional mechanisms and evaluating the biological knowledge captured by models. To address this demand, we introduce VenusX, the first large-scale benchmark for fine-grained functional annotation and function-based protein pairing at the residue, fragment, and domain levels. VenusX comprises three major task categories across six types of annotations, including residue-level binary classification, fragment-level multi-class classification, and pairwise functional similarity scoring for identifying critical active sites, binding sites, conserved sites, motifs, domains, and epitopes. The benchmark features over 878,000 samples curated from major open-source databases such as InterPro, BioLiP, and SAbDab. By providing mixed-family and cross-family splits at three sequence identity thresholds, our benchmark enables a comprehensive assessment of model performance on both in-distribution and out-of-distribution scenarios. For baseline evaluation, we assess a diverse set of popular and open-source models, including pre-trained protein language models, sequence-structure hybrids, structure-based methods, and alignment-based techniques. Their performance is reported across all benchmark datasets and evaluation settings using multiple metrics, offering a thorough comparison and a strong foundation for future research. Code and data are publicly available at https://github.com/ai4protein/VenusX.

The push toward large language models for biology (BioLM) has created a need for training corpora that can endow models with a genuine understanding of biology. However, existing biological resources, such as molecular databases, protein repositories, genomic annotations, single-cell atlases, and pathway databases, are scattered across heterogeneous formats and remain unorganized into a cohesive corpus for language model training. We present TheBioCollection, a 52.6B-token pre-training-scale corpus that converts these disparate resources into a unified, training-ready form spanning small molecules, proteins, genomic sequences, cells, and pathways. Beyond consolidating existing data, TheBioCollection enriches each record with tool-computed biological properties and introduces new instruction tasks for capabilities that current corpora barely cover. We pair the corpus with TheBioCollection-Eval, a matched suite probing recognition, generation, and prediction across molecular, protein, genomic, cellular, and cross-domain settings. Holding the base Gravity-16B-A3B architecture fixed, training on TheBioCollection more than doubles its overall score on TheBioCollection-Eval with gains in every domain, while leaving general linguistic ability nearly intact.

Large-taxonomy retrieval often assumes that the input already expresses the target concept. In many settings, however, the input is indirect evidence, such as a table cell whose meaning depends on its row, column, datatype, and context. We call this mismatch the retrieval readiness gap. Our analysis shows that the current index retrieves the target reliably when its semantics are explicit, while raw evidence often leaves it deep in the ranking. We propose Factorized Hypothesis Search (FHS), which maintains multiple partial interpretations over named semantic dimensions. These hypotheses support structured query rendering, multi-hypothesis retrieval, and dimension-level candidate verification. On both financial taxonomy tagging and CodiEsp clinical coding tasks, FHS achieves the best Recall@1, MRR, and final accuracy among the non-oracle methods. Replacing the factorized hypothesis path with a free-text ensemble causes the largest drop in head-ranking performance, while sequential refinement provides no additional gain over FHS's strong parallel first round.

Typed decision models answer schema-constrained questions about a text in one forward pass and return probabilities meant to be thresholded. We ask whether biomedical sentence encoders trained for retrieval are good starting points for such models. We present SBERT2S1, which converts Sentence-Transformers encoders into bi-encoder, cross-head (C) and prior-fused residual (PFR) decision models, together with BIODECIDE, a biomedical typed-decision suite, and MEDLINE-S1, 243k training decisions derived from NLM indexing. Across six parent-retriever pairs, retrieval training improves zero-shot matching of content-bearing options. After fine-tuning, its effect depends on the head: across five pairs and three training-set sizes, retrieval training significantly helps PFR, which keeps the retrieval prior, in 10 of 15 comparisons, but helps C in one and hurts it in five. A matched grid of two heads and five training objectives shows that C outperforms PFR under every objective, and that the released RLCD recipe of open System One models trails cross-entropy by 2.5-3.0 points. The deficit stems mainly from its reward normalisation, which inflates the noisy score-function term 3.6-15-fold; an unbiased leave-one-out estimator recovers most of the gap. After temperature scaling, no objective is clearly better calibrated than cross-entropy. We release the code, the MEDLINE-S1 labels and a model.

Learning effective protein representations is critical in a variety of tasks in biology such as predicting protein function or structure. Existing approaches usually pretrain protein language models on a large number of unlabeled amino acid sequences and then finetune the models with some labeled data in downstream tasks. Despite the effectiveness of sequence-based approaches, the power of pretraining on known protein structures, which are available in smaller numbers only, has not been explored for protein property prediction, though protein structures are known to be determinants of protein function. In this paper, we propose to pretrain protein representations according to their 3D structures. We first present a simple yet effective encoder to learn the geometric features of a protein. We pretrain the protein graph encoder by leveraging multiview contrastive learning and different self-prediction tasks. Experimental results on both function prediction and fold classification tasks show that our proposed pretraining methods outperform or are on par with the state-of-the-art sequence-based methods, while using much less pretraining data. Our implementation is available at https://github.com/DeepGraphLearning/GearNet.

The field of bioinformatics has seen significant progress, making the cross-modal text-molecule retrieval task increasingly vital. This task focuses on accurately retrieving molecule structures based on textual descriptions, by effectively aligning textual descriptions and molecules to assist researchers in identifying suitable molecular candidates. However, many existing approaches overlook the details inherent in molecule sub-structures. In this work, we introduce the Optimal TRansport-based Multi-grained Alignments model (ORMA), a novel approach that facilitates multi-grained alignments between textual descriptions and molecules. Our model features a text encoder and a molecule encoder. The text encoder processes textual descriptions to generate both token-level and sentence-level representations, while molecules are modeled as hierarchical heterogeneous graphs, encompassing atom, motif, and molecule nodes to extract representations at these three levels. A key innovation in ORMA is the application of Optimal Transport (OT) to align tokens with motifs, creating multi-token representations that integrate multiple token alignments with their corresponding motifs. Additionally, we employ contrastive learning to refine cross-modal alignments at three distinct scales: token-atom, multitoken-motif, and sentence-molecule, ensuring that the similarities between correctly matched text-molecule pairs are maximized while those of unmatched pairs are minimized. To our knowledge, this is the first attempt to explore alignments at both the motif and multi-token levels. Experimental results on the ChEBI-20 and PCdes datasets demonstrate that ORMA significantly outperforms existing state-of-the-art (SOTA) models.

Modern coding agents are usually evaluated by whether they eventually produce a correct patch, but patch generation depends on an earlier context-acquisition stage: finding the repository files needed for the task. We introduce Agent Retrieval Bench, a file-level benchmark for this upstream retrieval problem. Samples are built from real coding-workflow signals and evaluated against frozen base-commit repositories, with relevance defined by what an agent needs next rather than direct query-file semantic similarity. The benchmark covers four positive-retrieval tasks: code2test, comment2context, trace2code, and edit2ripple; a fifth subset evaluates selective retrieval using natural evidence-backed no-gold cases and counterfactual wrong-repository controls. Agent Retrieval Bench contains 427 samples across 25 repositories: 345 positive examples, 50 natural no-gold examples, and 32 counterfactual controls. The corpus includes 308 base-commit snapshots, 392,000 files, and 7.9 million chunks. We evaluate lexical retrieval, RepoMap, open-source embeddings, selective abstention, and logged agent context selection. No single retrieval family dominates: Qwen3-Embedding-4B has the best sample-weighted MRR on positive samples, Qwen3-Embedding-8B the best Recall@20, and RepoMap the best budgeted context yield at 8K tokens, with task-level winners differing substantially. Selective thresholds calibrated with counterfactual controls do not improve selective success on natural no-gold cases, revealing a calibration gap. Logged trajectories also miss every gold file on 27-35 percent of samples. A controlled seed-intervention pilot finds that retrieval-derived initial context yields higher file F1 with less post-seed exploration than random non-gold context, while oracle gold context shows substantial remaining headroom.

The annotation (assigning structural chemical identities) of MS/MS spectra remains a significant challenge due to the enormous molecular diversity in biological samples and the limited scope of reference databases. Currently, the vast majority of spectral measurements remain in the "dark chemical space" without structural annotations. To improve annotation, we propose MADGEN (Mass-spec Attends to De Novo Molecular GENeration), a scaffold-based method for de novo molecular structure generation guided by mass spectrometry data. MADGEN operates in two stages: scaffold retrieval and spectra-conditioned molecular generation starting with the scaffold. In the first stage, given an MS/MS spectrum, we formulate scaffold retrieval as a ranking problem and employ contrastive learning to align mass spectra with candidate molecular scaffolds. In the second stage, starting from the retrieved scaffold, we employ the MS/MS spectrum to guide an attention-based generative model to generate the final molecule. Our approach constrains the molecular generation search space, reducing its complexity and improving generation accuracy. We evaluate MADGEN on three datasets (NIST23, CANOPUS, and MassSpecGym) and evaluate MADGEN's performance with a predictive scaffold retriever and with an oracle retriever. We demonstrate the effectiveness of using attention to integrate spectral information throughout the generation process to achieve strong results with the oracle retriever.

The ability to generate proteins with desired functions is a central goal of computational biology. Although natural language can express diverse design objectives, existing protein generation methods often support only narrow tasks or make limited use of biological constraints. We develop InstructPro2 to translate natural-language design objectives into protein sequences while incorporating task-specific biological context. A text encoder captures the design instructions, while dedicated ligand and antigen encoders provide biological context to the sequence-generating decoder. For pretraining, we assemble InstructPro2Bench, comprising 205.7 million <function description, protein> pairs from UniProtKB. We subsequently adapt the model to ligand-binding protein and antibody design. On functional protein generation benchmarks, InstructPro2 outperforms Pinal, the strongest baseline, achieving a functional recovery F1 of 74.8 versus 62.2 and lowering global RMSD from 5.33A to 3.04A. For antibody design, the model obtains a DockQ score of 0.39, while ligand-binding protein design reaches a docking success rate of 72.6%. These findings highlight how integrating language-based instructions with biological conditioning can extend protein generation to distinct design settings.

We introduce a protein language model for determining the complete sequence of a peptide based on measurement of a limited set of amino acids. To date, protein sequencing relies on mass spectrometry, with some novel edman degregation based platforms able to sequence non-native peptides. Current protein sequencing techniques face limitations in accurately identifying all amino acids, hindering comprehensive proteome analysis. Our method simulates partial sequencing data by selectively masking amino acids that are experimentally difficult to identify in protein sequences from the UniRef database. This targeted masking mimics real-world sequencing limitations. We then modify and finetune a ProtBert derived transformer-based model, for a new downstream task predicting these masked residues, providing an approximation of the complete sequence. Evaluating on three bacterial Escherichia species, we achieve per-amino-acid accuracy up to 90.5% when only four amino acids ([KCYM]) are known. Structural assessment using AlphaFold and TM-score validates the biological relevance of our predictions. The model also demonstrates potential for evolutionary analysis through cross-species performance. This integration of simulated experimental constraints with computational predictions offers a promising avenue for enhancing protein sequence analysis, potentially accelerating advancements in proteomics and structural biology by providing a probabilistic reconstruction of the complete protein sequence from limited experimental data.

Retrieving relevant contexts from a large corpus is a crucial step for tasks such as open-domain question answering and fact checking. Although neural retrieval outperforms traditional methods like tf-idf and BM25, its performance degrades considerably when applied to out-of-domain data. Driven by the question of whether a neural retrieval model can be universal and perform robustly on a wide variety of problems, we propose a multi-task trained model. Our approach not only outperforms previous methods in the few-shot setting, but also rivals specialised neural retrievers, even when in-domain training data is abundant. With the help of our retriever, we improve existing models for downstream tasks and closely match or improve the state of the art on multiple benchmarks.

The integration of biomolecular modeling with natural language (BL) has emerged as a promising interdisciplinary area at the intersection of artificial intelligence, chemistry and biology. This approach leverages the rich, multifaceted descriptions of biomolecules contained within textual data sources to enhance our fundamental understanding and enable downstream computational tasks such as biomolecule property prediction. The fusion of the nuanced narratives expressed through natural language with the structural and functional specifics of biomolecules described via various molecular modeling techniques opens new avenues for comprehensively representing and analyzing biomolecules. By incorporating the contextual language data that surrounds biomolecules into their modeling, BL aims to capture a holistic view encompassing both the symbolic qualities conveyed through language as well as quantitative structural characteristics. In this review, we provide an extensive analysis of recent advancements achieved through cross modeling of biomolecules and natural language. (1) We begin by outlining the technical representations of biomolecules employed, including sequences, 2D graphs, and 3D structures. (2) We then examine in depth the rationale and key objectives underlying effective multi-modal integration of language and molecular data sources. (3) We subsequently survey the practical applications enabled to date in this developing research area. (4) We also compile and summarize the available resources and datasets to facilitate future work. (5) Looking ahead, we identify several promising research directions worthy of further exploration and investment to continue advancing the field. The related resources and contents are updating in https://github.com/QizhiPei/Awesome-Biomolecule-Language-Cross-Modeling.

Large Language Models (LLMs) have demonstrated exceptional performance in biochemical tasks, especially the molecule caption translation task, which aims to bridge the gap between molecules and natural language texts. However, previous methods in adapting LLMs to the molecule-caption translation task required extra domain-specific pre-training stages, suffered weak alignment between molecular and textual spaces, or imposed stringent demands on the scale of LLMs. To resolve the challenges, we propose In-Context Molecule Adaptation (ICMA), as a new paradigm allowing LLMs to learn the molecule-text alignment from context examples via In-Context Molecule Tuning. Specifically, ICMA incorporates the following three stages: Cross-modal Retrieval, Post-retrieval Re-ranking, and In-context Molecule Tuning. Initially, Cross-modal Retrieval utilizes BM25 Caption Retrieval and Molecule Graph Retrieval to retrieve informative context examples. Additionally, we also propose Post-retrieval Re-ranking with Sequence Reversal and Random Walk to further improve the quality of retrieval results. Finally, In-Context Molecule Tuning unlocks the in-context molecule learning capability of LLMs with retrieved examples and adapts the parameters of LLMs for the molecule-caption translation task. Experimental results demonstrate that ICMT can empower LLMs to achieve state-of-the-art or comparable performance without extra training corpora and intricate structures, showing that LLMs are inherently in-context molecule learners.

Protein biology focuses on the intricate relationships among sequences, structures, and functions. Deciphering protein functions is crucial for understanding biological processes, advancing drug discovery, and enabling synthetic biology applications. Since protein sequences determine tertiary structures, which in turn govern functions, integrating sequence and structure information is essential for accurate prediction of protein functions. Traditional protein language models (pLMs) have advanced protein-related tasks by learning representations from large-scale sequence and structure data. However, pLMs are limited in integrating broader contextual knowledge, particularly regarding functional modalities that are fundamental to protein biology. In contrast, large language models (LLMs) have exhibited outstanding performance in contextual understanding, reasoning, and generation across diverse domains. Leveraging these capabilities, STELLA is proposed as a multimodal LLM integrating protein sequence-structure representations with general knowledge to address protein function prediction. Through multimodal instruction tuning (MMIT) using the proposed OPI-Struc dataset, STELLA achieves state-of-the-art performance in two function-related tasks-functional description prediction (FP) and enzyme-catalyzed reaction prediction (EP). This study highlights the potential of multimodal LLMs as an alternative paradigm to pLMs to advance protein biology research.

The vast majority of retrieval models depend on vector inner products to produce a relevance score between a query and a document. This naturally limits the expressiveness of the relevance score that can be employed. We propose a new paradigm, instead of producing a vector to represent the query we produce a small neural network which acts as a learned relevance function. This small neural network takes in a representation of the document, in this paper we use a single vector, and produces a scalar relevance score. To produce the little neural network we use a hypernetwork, a network that produce the weights of other networks, as our query encoder or as we call it a Hypencoder. Experiments on in-domain search tasks show that Hypencoder is able to significantly outperform strong dense retrieval models and has higher metrics then reranking models and models an order of magnitude larger. Hypencoder is also shown to generalize well to out-of-domain search tasks. To assess the extent of Hypencoder's capabilities, we evaluate on a set of hard retrieval tasks including tip-of-the-tongue retrieval and instruction-following retrieval tasks and find that the performance gap widens substantially compared to standard retrieval tasks. Furthermore, to demonstrate the practicality of our method we implement an approximate search algorithm and show that our model is able to search 8.8M documents in under 60ms.

Deciphering protein function remains a fundamental challenge in protein representation learning. The task presents significant difficulties for protein language models (PLMs) due to the sheer volume of functional annotation categories and the highly imbalanced distribution of annotated instances across biological ontologies. Inspired by the remarkable success of reinforcement learning from human feedback (RLHF) in large language model (LLM) alignment, we propose AnnoDPO, a novel multi-modal framework for protein function prediction that leverages Direct Preference Optimization (DPO) to enhance annotation learning. Our methodology addresses the dual challenges of annotation scarcity and category imbalance through preference-aligned training objectives, establishing a new paradigm for biological knowledge integration in protein representation learning.

Large language models (LLMs) have grown in their usage to provide support for question answering across numerous disciplines. The models on their own have already shown promise for answering basic questions, however fail quickly where expert domain knowledge is required or the question is nuanced. Scientific research often involves searching for relevant literature, distilling pertinent information from that literature and analysing how the findings support or contradict one another. The information is often encapsulated in the full text body of research articles, rather than just in the abstracts. Statements within these articles frequently require the wider article context to be fully understood. We have built an LLM-based system that performs such search and distillation of information encapsulated in scientific literature, and we evaluate our keyword based search and information distillation system against a set of biology related questions from previously released literature benchmarks. We demonstrate sparse retrieval methods exhibit results close to state of the art without the need for dense retrieval, with its associated infrastructure and complexity overhead. We also show how to increase the coverage of relevant documents for literature review generation.

In this work, we aim to connect two research areas: instruction models and retrieval-based models. While instruction-tuned Large Language Models (LLMs) excel at extracting information from text, they are not suitable for semantic retrieval. Similarity search over embedding vectors allows to index and query vectors, but the similarity reflected in the embedding is sub-optimal for many use cases. We identify the task of retrieving sentences based on abstract descriptions of their content. We demonstrate the inadequacy of current text embeddings and propose an alternative model that significantly improves when used in standard nearest neighbor search. The model is trained using positive and negative pairs sourced through prompting an a large language model (LLM). While it is easy to source the training material from an LLM, the retrieval task cannot be performed by the LLM directly. This demonstrates that data from LLMs can be used not only for distilling more efficient specialized models than the original LLM, but also for creating new capabilities not immediately possible using the original model.

Proteins, as essential biomolecules, play a central role in biological processes, including metabolic reactions and DNA replication. Accurate prediction of their properties and functions is crucial in biological applications. Recent development of protein language models (pLMs) with supervised fine tuning provides a promising solution to this problem. However, the fine-tuned model is tailored for particular downstream prediction task, and achieving general-purpose protein understanding remains a challenge. In this paper, we introduce Structure-Enhanced Protein Instruction Tuning (SEPIT) framework to bridge this gap. Our approach integrates a noval structure-aware module into pLMs to inform them with structural knowledge, and then connects these enhanced pLMs to large language models (LLMs) to generate understanding of proteins. In this framework, we propose a novel two-stage instruction tuning pipeline that first establishes a basic understanding of proteins through caption-based instructions and then refines this understanding using a mixture of experts (MoEs) to learn more complex properties and functional information with the same amount of activated parameters. Moreover, we construct the largest and most comprehensive protein instruction dataset to date, which allows us to train and evaluate the general-purpose protein understanding model. Extensive experimental results on open-ended generation and closed-set answer tasks demonstrate the superior performance of SEPIT over both closed-source general LLMs and open-source LLMs trained with protein knowledge.

The design of protein sequences with desired functionalities is a fundamental task in protein engineering. Deep generative methods, such as autoregressive models and diffusion models, have greatly accelerated the discovery of novel protein sequences. However, these methods mainly focus on local or shallow residual semantics and suffer from low inference efficiency, large modeling space and high training cost. To address these challenges, we introduce ProtFlow, a fast flow matching-based protein sequence design framework that operates on embeddings derived from semantically meaningful latent space of protein language models. By compressing and smoothing the latent space, ProtFlow enhances performance while training on limited computational resources. Leveraging reflow techniques, ProtFlow enables high-quality single-step sequence generation. Additionally, we develop a joint design pipeline for the design scene of multichain proteins. We evaluate ProtFlow across diverse protein design tasks, including general peptides and long-chain proteins, antimicrobial peptides, and antibodies. Experimental results demonstrate that ProtFlow outperforms task-specific methods in these applications, underscoring its potential and broad applicability in computational protein sequence design and analysis.

Protein language models are a powerful tool for learning protein representations through pre-training on vast protein sequence datasets. However, traditional protein language models lack explicit structural supervision, despite its relevance to protein function. To address this issue, we introduce the integration of remote homology detection to distill structural information into protein language models without requiring explicit protein structures as input. We evaluate the impact of this structure-informed training on downstream protein function prediction tasks. Experimental results reveal consistent improvements in function annotation accuracy for EC number and GO term prediction. Performance on mutant datasets, however, varies based on the relationship between targeted properties and protein structures. This underscores the importance of considering this relationship when applying structure-aware training to protein function prediction tasks. Code and model weights are available at https://github.com/DeepGraphLearning/esm-s.

Information retrieval (IR) is essential in biomedical knowledge acquisition and clinical decision support. While recent progress has shown that language model encoders perform better semantic retrieval, training such models requires abundant query-article annotations that are difficult to obtain in biomedicine. As a result, most biomedical IR systems only conduct lexical matching. In response, we introduce BioCPT, a first-of-its-kind Contrastively Pre-trained Transformer model for zero-shot biomedical IR. To train BioCPT, we collected an unprecedented scale of 255 million user click logs from PubMed. With such data, we use contrastive learning to train a pair of closely-integrated retriever and re-ranker. Experimental results show that BioCPT sets new state-of-the-art performance on five biomedical IR tasks, outperforming various baselines including much larger models such as GPT-3-sized cpt-text-XL. In addition, BioCPT also generates better biomedical article and sentence representations for semantic evaluations. As such, BioCPT can be readily applied to various real-world biomedical IR tasks. BioCPT API and code are publicly available at https://github.com/ncbi/BioCPT.

Neural embedding models have become a fundamental component of modern information retrieval (IR) pipelines. These models produce a single embedding x in R^d per data-point, allowing for fast retrieval via highly optimized maximum inner product search (MIPS) algorithms. Recently, beginning with the landmark ColBERT paper, multi-vector models, which produce a set of embedding per data point, have achieved markedly superior performance for IR tasks. Unfortunately, using these models for IR is computationally expensive due to the increased complexity of multi-vector retrieval and scoring. In this paper, we introduce MUVERA (MUlti-VEctor Retrieval Algorithm), a retrieval mechanism which reduces multi-vector similarity search to single-vector similarity search. This enables the usage of off-the-shelf MIPS solvers for multi-vector retrieval. MUVERA asymmetrically generates Fixed Dimensional Encodings (FDEs) of queries and documents, which are vectors whose inner product approximates multi-vector similarity. We prove that FDEs give high-quality epsilon-approximations, thus providing the first single-vector proxy for multi-vector similarity with theoretical guarantees. Empirically, we find that FDEs achieve the same recall as prior state-of-the-art heuristics while retrieving 2-5times fewer candidates. Compared to prior state of the art implementations, MUVERA achieves consistently good end-to-end recall and latency across a diverse set of the BEIR retrieval datasets, achieving an average of 10% improved recall with 90% lower latency.

We report a flexible language-model based deep learning strategy, applied here to solve complex forward and inverse problems in protein modeling, based on an attention neural network that integrates transformer and graph convolutional architectures in a causal multi-headed graph mechanism, to realize a generative pretrained model. The model is applied to predict secondary structure content (per-residue level and overall content), protein solubility, and sequencing tasks. Further trained on inverse tasks, the model is rendered capable of designing proteins with these properties as target features. The model is formulated as a general framework, completely prompt-based, and can be adapted for a variety of downstream tasks. We find that adding additional tasks yields emergent synergies that the model exploits in improving overall performance, beyond what would be possible by training a model on each dataset alone. Case studies are presented to validate the method, yielding protein designs specifically focused on structural proteins, but also exploring the applicability in the design of soluble, antimicrobial biomaterials. While our model is trained to ultimately perform 8 distinct tasks, with available datasets it can be extended to solve additional problems. In a broader sense, this work illustrates a form of multiscale modeling that relates a set of ultimate building blocks (here, byte-level utf8 characters) to complex output. This materiomic scheme captures complex emergent relationships between universal building block and resulting properties via a synergizing learning capacity to express a set of potentialities embedded in the knowledge used in training, via the interplay of universality and diversity.

The question-answering system for Life science research, which is characterized by the rapid pace of discovery, evolving insights, and complex interactions among knowledge entities, presents unique challenges in maintaining a comprehensive knowledge warehouse and accurate information retrieval. To address these issues, we introduce BioRAG, a novel Retrieval-Augmented Generation (RAG) with the Large Language Models (LLMs) framework. Our approach starts with parsing, indexing, and segmenting an extensive collection of 22 million scientific papers as the basic knowledge, followed by training a specialized embedding model tailored to this domain. Additionally, we enhance the vector retrieval process by incorporating a domain-specific knowledge hierarchy, which aids in modeling the intricate interrelationships among each query and context. For queries requiring the most current information, BioRAG deconstructs the question and employs an iterative retrieval process incorporated with the search engine for step-by-step reasoning. Rigorous experiments have demonstrated that our model outperforms fine-tuned LLM, LLM with search engines, and other scientific RAG frameworks across multiple life science question-answering tasks.

Recent years have witnessed a surge in the development of protein structural tokenization methods, which chunk protein 3D structures into discrete or continuous representations. Structure tokenization enables the direct application of powerful techniques like language modeling for protein structures, and large multimodal models to integrate structures with protein sequences and functional texts. Despite the progress, the capabilities and limitations of these methods remain poorly understood due to the lack of a unified evaluation framework. We first introduce StructTokenBench, a framework that comprehensively evaluates the quality and efficiency of structure tokenizers, focusing on fine-grained local substructures rather than global structures, as typical in existing benchmarks. Our evaluations reveal that no single model dominates all benchmarking perspectives. Observations of codebook under-utilization led us to develop AminoAseed, a simple yet effective strategy that enhances codebook gradient updates and optimally balances codebook size and dimension for improved tokenizer utilization and quality. Compared to the leading model ESM3, our method achieves an average of 6.31% performance improvement across 24 supervised tasks, with sensitivity and utilization rates increased by 12.83% and 124.03%, respectively. Source code and model weights are available at https://github.com/KatarinaYuan/StructTokenBench

Protein-protein interaction (PPI) databases do not faithfully reflect biological realities. Instead, they are influenced by study and technical biases that distort certain protein and interaction attributes. Machine learning models can exploit these as learning shortcuts if the negative dataset is not constructed with care. So far, the shortcuts introduced during PPI dataset construction have only been examined in isolation. Here, we systematically characterize both reported and, to our knowledge, previously unreported biases in PPI datasets that lead machine learning models to learn shortcuts instead of biological signal. We analyze HIPPIE, IntAct, and STRING, dedicated PPI databases, as well as two datasets derived from 3D-structural information in the Protein Data Bank (PDB). We show that random data splitting introduces strong topological shortcuts. When train-test protein overlap is removed, the resulting datasets still retain usable shortcuts stemming from self-interactions, taxonomic identity, and functional relatedness, whose prevalence interestingly depends on the data source. We further show that sampling negatives from a set of high-confidence non-interactors, an intuitively appealing choice, can amplify the shortcut stemming from functional relatedness. To detect and mitigate these biases, we provide an open Nextflow pipeline that combines similarity-aware, data-loss-minimizing dataset splitting with bias-minimizing negative sampling, both formulated as integer linear programs. Its key concept of quantifying biases to minimize them through optimization-based negative sampling can, in principle, be extended to any machine learning problem where the pool of negative candidates is much larger than the positives and is thus of interest also beyond PPI prediction.

Protein language models (pLMs) pre-trained on vast protein sequence databases excel at various downstream tasks but lack the structural knowledge essential for many biological applications. To address this, we integrate structural insights from pre-trained protein graph neural networks (pGNNs) into pLMs through a latent-level contrastive learning task. This task aligns residue representations from pLMs with those from pGNNs across multiple proteins, enriching pLMs with inter-protein structural knowledge. Additionally, we incorporate a physical-level task that infuses intra-protein structural knowledge by optimizing pLMs to predict structural tokens. The proposed dual-task framework effectively incorporates both inter-protein and intra-protein structural knowledge into pLMs. Given the variability in the quality of protein structures in PDB, we further introduce a residue loss selection module, which uses a small model trained on high-quality structures to select reliable yet challenging residue losses for the pLM to learn. Applying our structure alignment method to the state-of-the-art ESM2 and AMPLIFY results in notable performance gains across a wide range of tasks, including a 12.7% increase in ESM2 contact prediction. The data, code, and resulting SaESM2 and SaAMPLIFY models will be released on Hugging Face.

Transformer architectures have proven to learn useful representations for protein classification and generation tasks. However, these representations present challenges in interpretability. In this work, we demonstrate a set of methods for analyzing protein Transformer models through the lens of attention. We show that attention: (1) captures the folding structure of proteins, connecting amino acids that are far apart in the underlying sequence, but spatially close in the three-dimensional structure, (2) targets binding sites, a key functional component of proteins, and (3) focuses on progressively more complex biophysical properties with increasing layer depth. We find this behavior to be consistent across three Transformer architectures (BERT, ALBERT, XLNet) and two distinct protein datasets. We also present a three-dimensional visualization of the interaction between attention and protein structure. Code for visualization and analysis is available at https://github.com/salesforce/provis.

As opposed to scaling-up protein language models (PLMs), we seek improving performance via protein-specific optimization. Although the proportionality between the language model size and the richness of its learned representations is validated, we prioritize accessibility and pursue a path of data-efficient, cost-reduced, and knowledge-guided optimization. Through over twenty experiments ranging from masking, architecture, and pre-training data, we derive insights from protein-specific experimentation into building a model that interprets the language of life, optimally. We present Ankh, the first general-purpose PLM trained on Google's TPU-v4 surpassing the state-of-the-art performance with fewer parameters (<10% for pre-training, <7% for inference, and <30% for the embedding dimension). We provide a representative range of structure and function benchmarks where Ankh excels. We further provide a protein variant generation analysis on High-N and One-N input data scales where Ankh succeeds in learning protein evolutionary conservation-mutation trends and introducing functional diversity while retaining key structural-functional characteristics. We dedicate our work to promoting accessibility to research innovation via attainable resources.

Learned sparse text embeddings have gained popularity due to their effectiveness in top-k retrieval and inherent interpretability. Their distributional idiosyncrasies, however, have long hindered their use in real-world retrieval systems. That changed with the recent development of approximate algorithms that leverage the distributional properties of sparse embeddings to speed up retrieval. Nonetheless, in much of the existing literature, evaluation has been limited to datasets with only a few million documents such as MSMARCO. It remains unclear how these systems behave on much larger datasets and what challenges lurk in larger scales. To bridge that gap, we investigate the behavior of state-of-the-art retrieval algorithms on massive datasets. We compare and contrast the recently-proposed Seismic and graph-based solutions adapted from dense retrieval. We extensively evaluate Splade embeddings of 138M passages from MsMarco-v2 and report indexing time and other efficiency and effectiveness metrics.

Dense retrieval models use bi-encoder network architectures for learning query and document representations. These representations are often in the form of a vector representation and their similarities are often computed using the dot product function. In this paper, we propose a new representation learning framework for dense retrieval. Instead of learning a vector for each query and document, our framework learns a multivariate distribution and uses negative multivariate KL divergence to compute the similarity between distributions. For simplicity and efficiency reasons, we assume that the distributions are multivariate normals and then train large language models to produce mean and variance vectors for these distributions. We provide a theoretical foundation for the proposed framework and show that it can be seamlessly integrated into the existing approximate nearest neighbor algorithms to perform retrieval efficiently. We conduct an extensive suite of experiments on a wide range of datasets, and demonstrate significant improvements compared to competitive dense retrieval models.

Time-series diagnostic systems rarely rely on retrieving relevant historical cases, and when they do, retrieval is evaluated only indirectly through downstream prediction. We introduce READ-Bench, a benchmark for historical-case retrieval across 12 diagnostic datasets, centered on multivariate time series, that defines relevance by shared fault or event type rather than signal shape, so visually different traces of the same fault count as relevant while similar-looking traces of different faults do not. Treating retrieval as a base retriever followed by a reranker, we evaluate classical distances, symbolic retrievers, self-supervised and foundation-model embedders, and their fusion, plus label-aware and language-model rerankers, under one protocol that varies supervision, pollution, and corpus scale with significance testing. Under a common channel-independent interface, pretrained representations offer no statistically detectable advantage over strong classical and symbolic baselines for search alone. The decisive factor is a small amount of resolved-case supervision at reranking, namely a Gaussian-process reranker that propagates a few neighbor labels in embedding space, which helps far more than more sophisticated representations or language-model reasoning and holds under pollution and at full corpus scale. Guided by these findings, we fuse a normal-residual-scored embedder with a dynamic time warping leg via reciprocal-rank fusion, then rerank with the Gaussian-process reranker, improving NDCG@10 over its own search stage on all 12 datasets, by +0.11 from reranking and +0.16 over the strongest single base retriever.

Multiple sequence alignments (MSAs) of proteins encode rich biological information and have been workhorses in bioinformatic methods for tasks like protein design and protein structure prediction for decades. Recent breakthroughs like AlphaFold2 that use transformers to attend directly over large quantities of raw MSAs have reaffirmed their importance. Generation of MSAs is highly computationally intensive, however, and no datasets comparable to those used to train AlphaFold2 have been made available to the research community, hindering progress in machine learning for proteins. To remedy this problem, we introduce OpenProteinSet, an open-source corpus of more than 16 million MSAs, associated structural homologs from the Protein Data Bank, and AlphaFold2 protein structure predictions. We have previously demonstrated the utility of OpenProteinSet by successfully retraining AlphaFold2 on it. We expect OpenProteinSet to be broadly useful as training and validation data for 1) diverse tasks focused on protein structure, function, and design and 2) large-scale multimodal machine learning research.

Although existing neural retrieval models reveal promising results when training data is abundant and the performance keeps improving as training data increases, collecting high-quality annotated data is prohibitively costly. To this end, we introduce a novel noisy self-training framework combined with synthetic queries, showing that neural retrievers can be improved in a self-evolution manner with no reliance on any external models. Experimental results show that our method improves consistently over existing methods on both general-domain (e.g., MS-MARCO) and out-of-domain (i.e., BEIR) retrieval benchmarks. Extra analysis on low-resource settings reveals that our method is data efficient and outperforms competitive baselines, with as little as 30% of labelled training data. Further extending the framework for reranker training demonstrates that the proposed method is general and yields additional gains on tasks of diverse domains.Source code is available at \url{https://github.com/Fantabulous-J/Self-Training-DPR}

We present AMix-2, a protein-text foundation model that establishes protein as a native modality in large language models (LLMs), unifying protein understanding and sequence design within a single foundation model. AMix-2 is built upon two key ideas: (1) a unified protein-text formulation that embeds natural language and protein sequence in a shared token space, enabling one model to perform biological reasoning and conditional design instead of separate downstream task-specialized models; and (2) a block-wise diffusion language modeling backbone that combines causal generation across blocks with bidirectional context and iterative refinement within blocks. This scheme better matches the intrinsic nature of proteins than a strict left-to-right factorization. To evaluate protein foundation models under realistic generalization settings, we further introduce ProteinArena, a comprehensive benchmark with time-aware and homology-aware protocols across various understanding and design tasks, and with baselines covering classical bioinformatics tools, protein-specialized models and LLMs. On ProteinArena, AMix-2 outperforms frontier LLMs and demonstrates competitive performance to task-specific protein models. Controlled experiments further show that the diffusion-based paradigm generally surpasses its autoregressive counterpart, highlighting the advantage of flexible generation order for protein sequences. We release both AMix-2 and ProteinArena to facilitate open research in protein foundation models.

Machine learning is widely used to analyze biological sequence data. Non-sequential models such as SVMs or feed-forward neural networks are often used although they have no natural way of handling sequences of varying length. Recurrent neural networks such as the long short term memory (LSTM) model on the other hand are designed to handle sequences. In this study we demonstrate that LSTM networks predict the subcellular location of proteins given only the protein sequence with high accuracy (0.902) outperforming current state of the art algorithms. We further improve the performance by introducing convolutional filters and experiment with an attention mechanism which lets the LSTM focus on specific parts of the protein. Lastly we introduce new visualizations of both the convolutional filters and the attention mechanisms and show how they can be used to extract biological relevant knowledge from the LSTM networks.

Large Language Models (LLMs), including GPT-x and LLaMA2, have achieved remarkable performance in multiple Natural Language Processing (NLP) tasks. Under the premise that protein sequences constitute the protein language, Protein Large Language Models (ProLLMs) trained on protein corpora excel at de novo protein sequence generation. However, as of now, unlike LLMs in NLP, no ProLLM is capable of multiple tasks in the Protein Language Processing (PLP) field. This prompts us to delineate the inherent limitations in current ProLLMs: (i) the lack of natural language capabilities, (ii) insufficient instruction understanding, and (iii) high training resource demands. To address these challenges, we introduce a training framework to transform any general LLM into a ProLLM capable of handling multiple PLP tasks. Specifically, our framework utilizes low-rank adaptation and employs a two-stage training approach, and it is distinguished by its universality, low overhead, and scalability. Through training under this framework, we propose the ProLLaMA model, the first known ProLLM to handle multiple PLP tasks simultaneously. Experiments show that ProLLaMA achieves state-of-the-art results in the unconditional protein sequence generation task. In the controllable protein sequence generation task, ProLLaMA can design novel proteins with desired functionalities. In the protein property prediction task, ProLLaMA achieves nearly 100\% accuracy across many categories. The latter two tasks are beyond the reach of other ProLLMs. Code is available at https://github.com/Lyu6PosHao/ProLLaMA.

Learned multivector representations power modern search systems with strong retrieval effectiveness, but their real-world use is limited by the high cost of exhaustive token-level retrieval. Therefore, most systems adopt a gather-and-refine strategy, where a lightweight gather phase selects candidates for full scoring. However, this approach requires expensive searches over large token-level indexes and often misses the documents that would rank highest under full similarity. In this paper, we reproduce several state-of-the-art multivector retrieval methods on two publicly available datasets, providing a clear picture of the current multivector retrieval field and observing the inefficiency of token-level gathering. Building on top of that, we show that replacing the token-level gather phase with a single-vector document retriever -- specifically, a learned sparse retriever (LSR) -- produces a smaller and more semantically coherent candidate set. This recasts the gather-and-refine pipeline into the well-established two-stage retrieval architecture. As retrieval latency decreases, query encoding with two neural encoders becomes the dominant computational bottleneck. To mitigate this, we integrate recent inference-free LSR methods, demonstrating that they preserve the retrieval effectiveness of the dual-encoder pipeline while substantially reducing query encoding time. Finally, we investigate multiple reranking configurations that balance efficiency, memory, and effectiveness, and we introduce two optimization techniques that prune low-quality candidates early. Empirical results show that these techniques improve retrieval efficiency by up to 1.8times with no loss in quality. Overall, our two-stage approach achieves over 24times speedup over the state-of-the-art multivector retrieval systems, while maintaining comparable or superior retrieval quality.

The vast majority of biological sequences encode unknown functions and bear little resemblance to experimentally characterized proteins, limiting both our understanding of biology and our ability to harness functional potential for the bioeconomy. Predicting enzyme function from sequence remains a central challenge in computational biology, complicated by low sequence diversity and imbalanced label support in publicly available datasets. Models trained on these data can overestimate performance and fail to generalize. To address this, we introduce GRIMM (Genetic stRatification for Inference in Molecular Modeling), a benchmark for enzyme function prediction that employs genetic stratification: sequences are clustered by similarity and clusters are assigned exclusively to training, validation, or test sets. This ensures that sequences from the same cluster do not appear in multiple partitions. GRIMM produces multiple test sets: a closed-set test with the same label distribution as training (Test-1) and an open-set test containing novel labels (Test-2), serving as a realistic out-of-distribution proxy for discovering novel enzyme functions. While demonstrated on enzymes, this approach is generalizable to any sequence-based classification task where inputs can be clustered by similarity. By formalizing a splitting strategy often used implicitly, GRIMM provides a unified and reproducible framework for closed- and open-set evaluation. The method is lightweight, requiring only sequence clustering and label annotations, and can be adapted to different similarity thresholds, data scales, and biological tasks. GRIMM enables more realistic evaluation of functional prediction models on both familiar and unseen classes and establishes a benchmark that more faithfully assesses model performance and generalizability.

Protein language models (PLMs) have emerged as powerful tools to detect complex patterns of protein sequences. However, the capability of PLMs to fully capture information on protein sequences might be limited by focusing on single pre-training tasks. Although adding data modalities or supervised objectives can improve the performance of PLMs, pre-training often remains focused on denoising corrupted sequences. To push the boundaries of PLMs, our research investigated a multi-task pre-training strategy. We developed Ankh3, a model jointly optimized on two objectives: masked language modeling with multiple masking probabilities and protein sequence completion relying only on protein sequences as input. This multi-task pre-training demonstrated that PLMs can learn richer and more generalizable representations solely from protein sequences. The results demonstrated improved performance in downstream tasks, such as secondary structure prediction, fluorescence, GB1 fitness, and contact prediction. The integration of multiple tasks gave the model a more comprehensive understanding of protein properties, leading to more robust and accurate predictions.

Precise retrieval of scientific information is fundamentally constrained by long-tailed concepts and high fact-sensitivity of scientific corpora. These challenges often limit the effectiveness of dense retrievers and hallucination-prone LLM augmentation. To address this, we present REPAIR, a self-evolving data augmentation framework for scientific dense retrievers. REPAIR iteratively synthesizes training data to address knowledge gaps by cycling through diagnosis of long-tail concepts, API-guided evidence expansion, and differentiation via hard negative mining. This process effectively grounds retrieval in factual reality to resolve fine-grained distinctions. Extensive experiments demonstrate that REPAIR significantly outperforms 19 strong baselines on nine materials science and biomedical benchmarks. Our work highlights that diagnosing and factually augmenting data to long-tail deficits is essential for robust scientific retrieval.

Learned sparse representations form an attractive class of contextual embeddings for text retrieval. That is so because they are effective models of relevance and are interpretable by design. Despite their apparent compatibility with inverted indexes, however, retrieval over sparse embeddings remains challenging. That is due to the distributional differences between learned embeddings and term frequency-based lexical models of relevance such as BM25. Recognizing this challenge, a great deal of research has gone into, among other things, designing retrieval algorithms tailored to the properties of learned sparse representations, including approximate retrieval systems. In fact, this task featured prominently in the latest BigANN Challenge at NeurIPS 2023, where approximate algorithms were evaluated on a large benchmark dataset by throughput and recall. In this work, we propose a novel organization of the inverted index that enables fast yet effective approximate retrieval over learned sparse embeddings. Our approach organizes inverted lists into geometrically-cohesive blocks, each equipped with a summary vector. During query processing, we quickly determine if a block must be evaluated using the summaries. As we show experimentally, single-threaded query processing using our method, Seismic, reaches sub-millisecond per-query latency on various sparse embeddings of the MS MARCO dataset while maintaining high recall. Our results indicate that Seismic is one to two orders of magnitude faster than state-of-the-art inverted index-based solutions and further outperforms the winning (graph-based) submissions to the BigANN Challenge by a significant margin.

Classifying protein topology is essential for deciphering biological function, but progress is held back by the lack of large-scale benchmarks that avoid duplicates and by models that do not scale well. We introduce TEDBench, a large-scale, non-redundant benchmark for protein fold classification constructed from the Encyclopedia of Domains (TED) and Foldseek-clustered AlphaFold structures. We show that on TEDBench, current protein representation learning methods either require very large models or fail to deliver strong performance. To address this challenge, we propose Masked Invariant Autoencoders (MiAE), a self-supervised framework for protein structure representation learning. MiAE uses an extremely high masking ratio of up to 90% with an SE(3)-invariant encoder and a lightweight decoder that reconstructs backbone coordinates from the latent representation and mask tokens. MiAE scales well and outperforms supervised counterparts and state-of-the-art baselines on TEDBench, establishing a strong recipe for protein fold classification. To test transfer beyond AlphaFold structures, we further benchmark on a curated dataset from experimental structures of CATH v4.4. TEDBench is available at https://github.com/BorgwardtLab/TEDBench.

Public viral genome resources such as the National Center for Biotechnology Information (NCBI) Virus database are central to outbreak response, evolutionary analysis, vaccine design, and genomic surveillance. Yet many high-value retrieval workflows remain optimized for interactive use rather than deterministic, reproducible programmatic interfaces. This creates a challenge for Large Language Model (LLM)-based scientific agents, where errors in metadata interpretation, filtering logic, or retrieval can propagate into incorrect datasets. To evaluate agentic viral data retrieval, we built VirBench, a manually curated benchmark of 120 queries spanning diverse pathogens, taxonomic levels, and metadata filters. When autonomous AI systems, including Biomni, Claude, GPT, and Edison Analysis, were tasked with these queries without a dedicated retrieval layer, performance varied widely: mean accuracy ranged from 16.9% for Claude Sonnet 4 to 91.3% for GPT-5.5, with newer frontier models showing progress but residual errors remaining consequential. To address this, we built gget virus, a deterministic query framework that formalizes NCBI Virus-style filtering as a reproducible programmatic system. By staging retrieval, applying metadata constraints before sequence download, and retrieving structured GenBank records, gget virus reduces data transfer by more than 98% for high-volume queries while preserving exact-match semantics. Instructing autonomous AI systems to use gget virus increased accuracy to at least 90.0% across all evaluated systems and up to 99.7% for GPT-5.5, improved response stability to 0.92-1.00, reduced error magnitude, and generally decreased runtime and tool calls. Together, this work establishes deterministic data access as critical infrastructure for reliable agentic science and provides a reproducible retrieval layer for robust human- and AI-driven viral genomics workflows.

With the rapid spread of retrieval-augmented generation and semantic search, choosing the right embedding and retrieval configuration is increasingly hard. Large retrieval benchmarks are comprehensive but too heavy to rerun during development, and there is little infrastructure for comparing production settings--dimensionality reduction, quantization, reranking--across many models under identical conditions. We present HAKARI-Bench, a lightweight benchmark that reconstructs existing retrieval suites into small datasets (Nano-sets): 35 benchmarks and 551 tasks across 43 languages in a unified format, enabling same-condition, model-agnostic comparison of five retrieval families (BM25, dense, sparse, late interaction, rerankers) and their efficiency variants. Across 55 models, its overall ranking reproduces the official MTEB retrieval v2, MMTEB v2 retrieval, and English BEIR (full) at Spearman >0.97. HAKARI-Bench does not replace full evaluation; it enables rapid model selection, regression detection, and reading the quality-efficiency Pareto frontier. Code, data, and leaderboard are released under the MIT license.

Recent research in representation learning utilizes large databases of proteins or molecules to acquire knowledge of drug and protein structures through unsupervised learning techniques. These pre-trained representations have proven to significantly enhance the accuracy of subsequent tasks, such as predicting the affinity between drugs and target proteins. In this study, we demonstrate that by incorporating knowledge graphs from diverse sources and modalities into the sequences or SMILES representation, we can further enrich the representation and achieve state-of-the-art results on established benchmark datasets. We provide preprocessed and integrated data obtained from 7 public sources, which encompass over 30M triples. Additionally, we make available the pre-trained models based on this data, along with the reported outcomes of their performance on three widely-used benchmark datasets for drug-target binding affinity prediction found in the Therapeutic Data Commons (TDC) benchmarks. Additionally, we make the source code for training models on benchmark datasets publicly available. Our objective in releasing these pre-trained models, accompanied by clean data for model pretraining and benchmark results, is to encourage research in knowledge-enhanced representation learning.

Protein language models are trained primarily with masked language modeling (MLM), which predicts amino-acid identities at masked positions. We ask whether latent-space prediction can complement these token-level objectives under matched wall-clock budget. Across pretrained and random-init protein sequence encoders at 35--150M parameters, we find that the best protein-JEPA design is not all-position latent prediction but a variant: predicting latent targets only at masked positions, and retaining the MLM cross-entropy. We call this recipe masked-position MLM+JEPA. On a 16-task downstream suite (15 frozen linear probes plus SCOPe-40 zero-shot fold retrieval), under matched wall-clock budgets, this recipe wins more tasks than it loses against MLM-only continuation: 10 wins / 3 losses / 3 ties (hereafter W/L/T) on pretrained ESM2-35M, 11/2/3 on ESM2-150M while results in pretraining from scratch are mixed (6/8/2). Gains are seen for multiple models on 11 of 16 tasks, including stability, etaβeta-lactamase fitness, variant effect, intrinsic disorder, remote homology, enzyme classification, and SCOPe-40 fold retrieval. Tasks with more losses than wins are Fluorescence (TAPE) and Peptide-HLA Binding. All-position MLM+JEPA matches MLM-only overall but does not reproduce the masked-position gains. JEPA-only (no MLM) collapses in nearly every experiment. We conclude that JEPA, when combined with MLM, is competitive and can outperform pure MLM in pretraining and continued training, even under matched wall-clock budgets.

Recently, the application of the retrieval-augmented Large Language Models (LLMs) in specific domains has gained significant attention, especially in biopharmaceuticals. However, in this context, there is no benchmark specifically designed for biopharmaceuticals to evaluate LLMs. In this paper, we introduce the Biopharmaceuticals Retrieval-Augmented Generation Evaluation (BRAGE) , the first benchmark tailored for evaluating LLMs' Query and Reference Understanding Capability (QRUC) in the biopharmaceutical domain, available in English, French, German and Chinese. In addition, Traditional Question-Answering (QA) metrics like accuracy and exact match fall short in the open-ended retrieval-augmented QA scenarios. To address this, we propose a citation-based classification method to evaluate the QRUC of LLMs to understand the relationship between queries and references. We apply this method to evaluate the mainstream LLMs on BRAGE. Experimental results show that there is a significant gap in the biopharmaceutical QRUC of mainstream LLMs, and their QRUC needs to be improved.

Current Large Language Models (LLMs) for understanding proteins primarily treats amino acid sequences as a text modality. Meanwhile, Protein Language Models (PLMs), such as ESM-2, have learned massive sequential evolutionary knowledge from the universe of natural protein sequences. Furthermore, structure-based encoders like ProteinMPNN learn the structural information of proteins through Graph Neural Networks. However, whether the incorporation of protein encoders can enhance the protein understanding of LLMs has not been explored. To bridge this gap, we propose EvoLlama, a multimodal framework that connects a structure-based encoder, a sequence-based protein encoder and an LLM for protein understanding. EvoLlama consists of a ProteinMPNN structure encoder, an ESM-2 protein sequence encoder, a multimodal projector to align protein and text representations and a Llama-3 text decoder. To train EvoLlama, we fine-tune it on protein-oriented instructions and protein property prediction datasets verbalized via natural language instruction templates. Our experiments show that EvoLlama's protein understanding capabilities have been significantly enhanced, outperforming other fine-tuned protein-oriented LLMs in zero-shot settings by an average of 1%-8% and surpassing the state-of-the-art baseline with supervised fine-tuning by an average of 6%. On protein property prediction datasets, our approach achieves promising results that are competitive with state-of-the-art task-specific baselines. We will release our code in a future version.

Understanding biomolecular function requires characterizing three-dimensional structure and conformational variability, for which cryogenic electron microscopy (cryo-EM) is a powerful tool. Cryo-EM produces noisy two-dimensional particle images in which molecular structure, particle pose, and imaging conditions are jointly encoded. Recovering biological information from these observations spans inverse problems including pose estimation, heterogeneity analysis, and reconstruction. These tasks are usually addressed independently despite shared protein structure and image formation, motivating a common representation across inverse problems. Since biologically meaningful differences may be spatially localized, we study self-distillation with complementary global and masked patch objectives. Because experimental dataset discrimination can reflect acquisition-specific cues, we develop controlled synthetic and experimental evaluations and find that structural discrimination benefits from dense spatial features. We introduce the EMber family of vision transformers, pre-trained on >50 million experimental particle images from 214 EMPIAR datasets together with simulated projections from 268,000 molecular assemblies. EMber improves upon existing methods at conformational and compositional discrimination by 14.85 and 14.26 percentage points, estimates conformational populations to within 1.59pp error with a linear probe, and produces particle assignments yielding reference-quality reconstructions in fewer epochs. We demonstrate how to learn representations that capture biological information for use across multiple cryo-EM inverse problems.

We propose ListT5, a novel reranking approach based on Fusion-in-Decoder (FiD) that handles multiple candidate passages at both train and inference time. We also introduce an efficient inference framework for listwise ranking based on m-ary tournament sort with output caching. We evaluate and compare our model on the BEIR benchmark for zero-shot retrieval task, demonstrating that ListT5 (1) outperforms the state-of-the-art RankT5 baseline with a notable +1.3 gain in the average NDCG@10 score, (2) has an efficiency comparable to pointwise ranking models and surpasses the efficiency of previous listwise ranking models, and (3) overcomes the lost-in-the-middle problem of previous listwise rerankers. Our code, model checkpoints, and the evaluation framework are fully open-sourced at https://github.com/soyoung97/ListT5.

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the high-throughput analysis of protein composition in biological tissues. Many deep learning methods have been developed for de novo peptide sequencing task, i.e., predicting the peptide sequence for the observed mass spectrum. However, two key challenges seriously hinder the further advancement of this important task. Firstly, since there is no consensus for the evaluation datasets, the empirical results in different research papers are often not comparable, leading to unfair comparison. Secondly, the current methods are usually limited to amino acid-level or peptide-level precision and recall metrics. In this work, we present the first unified benchmark NovoBench for de novo peptide sequencing, which comprises diverse mass spectrum data, integrated models, and comprehensive evaluation metrics. Recent impressive methods, including DeepNovo, PointNovo, Casanovo, InstaNovo, AdaNovo and pi-HelixNovo are integrated into our framework. In addition to amino acid-level and peptide-level precision and recall, we evaluate the models' performance in terms of identifying post-tranlational modifications (PTMs), efficiency and robustness to peptide length, noise peaks and missing fragment ratio, which are important influencing factors while seldom be considered. Leveraging this benchmark, we conduct a large-scale study of current methods, report many insightful findings that open up new possibilities for future development.

We investigate the exploitation of both lexical and neural relevance signals for ad-hoc passage retrieval. Our exploration involves a large-scale training dataset in which dense neural representations of MS-MARCO queries and passages are complemented and integrated with 253 hand-crafted lexical features extracted from the same corpus. Blending of the relevance signals from the two different groups of features is learned by a classical Learning-to-Rank (LTR) model based on a forest of decision trees. To evaluate our solution, we employ a pipelined architecture where a dense neural retriever serves as the first stage and performs a nearest-neighbor search over the neural representations of the documents. Our LTR model acts instead as the second stage that re-ranks the set of candidates retrieved by the first stage to enhance effectiveness. The results of reproducible experiments conducted with state-of-the-art dense retrievers on publicly available resources show that the proposed solution significantly enhances the end-to-end ranking performance while relatively minimally impacting efficiency. Specifically, we achieve a boost in nDCG@10 of up to 11% with an increase in average query latency of only 4.3%. This confirms the advantage of seamlessly combining two distinct families of signals that mutually contribute to retrieval effectiveness.

Current pre-trained language model approaches to information retrieval can be broadly divided into two categories: sparse retrievers (to which belong also non-neural approaches such as bag-of-words methods, e.g., BM25) and dense retrievers. Each of these categories appears to capture different characteristics of relevance. Previous work has investigated how relevance signals from sparse retrievers could be combined with those from dense retrievers via interpolation. Such interpolation would generally lead to higher retrieval effectiveness. In this paper we consider the problem of combining the relevance signals from sparse and dense retrievers in the context of Pseudo Relevance Feedback (PRF). This context poses two key challenges: (1) When should interpolation occur: before, after, or both before and after the PRF process? (2) Which sparse representation should be considered: a zero-shot bag-of-words model (BM25), or a learnt sparse representation? To answer these questions we perform a thorough empirical evaluation considering an effective and scalable neural PRF approach (Vector-PRF), three effective dense retrievers (ANCE, TCTv2, DistillBERT), and one state-of-the-art learnt sparse retriever (uniCOIL). The empirical findings from our experiments suggest that, regardless of sparse representation and dense retriever, interpolation both before and after PRF achieves the highest effectiveness across most datasets and metrics.

Chemical similarity searches are widely used in-silico methods for identifying new drug-like molecules. These methods have historically relied on structure-based comparisons to compute molecular similarity. Here, we use a chemical language model to create a vector-based chemical search. We extend implementations by creating a prompt engineering strategy that utilizes two different chemical string representation algorithms: one for the query and the other for the database. We explore this method by reviewing the search results from five drug-like query molecules (penicillin G, nirmatrelvir, zidovudine, lysergic acid diethylamide, and fentanyl) and three dye-like query molecules (acid blue 25, avobenzone, and 2-diphenylaminocarbazole). We find that this novel method identifies molecules that are functionally similar to the query, indicated by the associated patent literature, and that many of these molecules are structurally distinct from the query, making them unlikely to be found with traditional chemical similarity search methods. This method may aid in the discovery of novel structural classes of molecules that achieve target functionality.

Rapid progress in deep learning has spurred its application to bioinformatics problems including protein structure prediction and design. In classic machine learning problems like computer vision, progress has been driven by standardized data sets that facilitate fair assessment of new methods and lower the barrier to entry for non-domain experts. While data sets of protein sequence and structure exist, they lack certain components critical for machine learning, including high-quality multiple sequence alignments and insulated training / validation splits that account for deep but only weakly detectable homology across protein space. We have created the ProteinNet series of data sets to provide a standardized mechanism for training and assessing data-driven models of protein sequence-structure relationships. ProteinNet integrates sequence, structure, and evolutionary information in programmatically accessible file formats tailored for machine learning frameworks. Multiple sequence alignments of all structurally characterized proteins were created using substantial high-performance computing resources. Standardized data splits were also generated to emulate the difficulty of past CASP (Critical Assessment of protein Structure Prediction) experiments by resetting protein sequence and structure space to the historical states that preceded six prior CASPs. Utilizing sensitive evolution-based distance metrics to segregate distantly related proteins, we have additionally created validation sets distinct from the official CASP sets that faithfully mimic their difficulty. ProteinNet thus represents a comprehensive and accessible resource for training and assessing machine-learned models of protein structure.

Proteins are essential macromolecules defined by their amino acid sequences, which determine their three-dimensional structures and, consequently, their functions in all living organisms. Therefore, generative protein modeling necessitates a multimodal approach to simultaneously model, understand, and generate both sequences and structures. However, existing methods typically use separate models for each modality, limiting their ability to capture the intricate relationships between sequence and structure. This results in suboptimal performance in tasks that requires joint understanding and generation of both modalities. In this paper, we introduce DPLM-2, a multimodal protein foundation model that extends discrete diffusion protein language model (DPLM) to accommodate both sequences and structures. To enable structural learning with the language model, 3D coordinates are converted to discrete tokens using a lookup-free quantization-based tokenizer. By training on both experimental and high-quality synthetic structures, DPLM-2 learns the joint distribution of sequence and structure, as well as their marginals and conditionals. We also implement an efficient warm-up strategy to exploit the connection between large-scale evolutionary data and structural inductive biases from pre-trained sequence-based protein language models. Empirical evaluation shows that DPLM-2 can simultaneously generate highly compatible amino acid sequences and their corresponding 3D structures eliminating the need for a two-stage generation approach. Moreover, DPLM-2 demonstrates competitive performance in various conditional generation tasks, including folding, inverse folding, and scaffolding with multimodal motif inputs, as well as providing structure-aware representations for predictive tasks.

Generative machine learning models are increasingly being used to design novel proteins for therapeutic and biotechnological applications. However, the current methods mostly focus on the design of proteins with a fixed backbone structure, which leads to their limited ability to account for protein flexibility, one of the crucial properties for protein function. Learning to engineer protein flexibility is problematic because the available data are scarce, heterogeneous, and costly to obtain using computational as well as experimental methods. Our contributions to address this problem are three-fold. First, we comprehensively compare methods for quantifying protein flexibility and identify data relevant to learning. Second, we design and train flexibility predictors utilizing sequential or both sequential and structural information on the input. We overcome the data scarcity issue by leveraging a pre-trained protein language model. Third, we introduce a method for fine-tuning a protein inverse folding model to steer it toward desired flexibility in specified regions. We demonstrate that our method Flexpert-Design enables guidance of inverse folding models toward increased flexibility. This opens up new possibilities for protein flexibility engineering and the development of proteins with enhanced biological activities.

Protein structure tokenization converts 3D structures into discrete or vectorized representations, enabling the integration of structural and sequence data. Despite many recent works on structure tokenization, the properties of the underlying discrete representations are not well understood. In this work, we first demonstrate that the successful utilization of structural tokens in a language model for structure prediction depends on using rich, pre-trained sequence embeddings to bridge the semantic gap between the sequence and structural "language". The analysis of the structural vocabulary itself then reveals significant semantic redundancy, where multiple distinct tokens correspond to nearly identical local geometries, acting as "structural synonyms". This redundancy, rather than being a flaw, can be exploited with a simple "synonym swap" strategy to generate diverse conformational ensembles by perturbing a predicted structure with its structural synonyms. This computationally lightweight method accurately recapitulates protein flexibility, performing competitively with state-of-the-art models. Our study provides fundamental insights into the nature of discrete protein structure representations and introduces a powerful, near-instantaneous method for modeling protein dynamics. Source code is available in https://github.com/IDEA-XL/TokenMD.

Attention-based models trained on protein sequences have demonstrated incredible success at classification and generation tasks relevant for artificial intelligence-driven protein design. However, we lack a sufficient understanding of how very large-scale models and data play a role in effective protein model development. We introduce a suite of protein language models, named ProGen2, that are scaled up to 6.4B parameters and trained on different sequence datasets drawn from over a billion proteins from genomic, metagenomic, and immune repertoire databases. ProGen2 models show state-of-the-art performance in capturing the distribution of observed evolutionary sequences, generating novel viable sequences, and predicting protein fitness without additional finetuning. As large model sizes and raw numbers of protein sequences continue to become more widely accessible, our results suggest that a growing emphasis needs to be placed on the data distribution provided to a protein sequence model. We release the ProGen2 models and code at https://github.com/salesforce/progen.

Biomedical text mining and question-answering are essential yet highly demanding tasks, particularly in the face of the exponential growth of biomedical literature. In this work, we present our participation in the 13th edition of the BioASQ challenge, which involves biomedical semantic question-answering for Task 13b and biomedical question-answering for developing topics for the Synergy task. We deploy a selection of open-source large language models (LLMs) as retrieval-augmented generators to answer biomedical questions. Various models are used to process the questions. A majority voting system combines their output to determine the final answer for Yes/No questions, while for list and factoid type questions, the union of their answers in used. We evaluated 13 state-of-the-art open source LLMs, exploring all possible model combinations to contribute to the final answer, resulting in tailored LLM pipelines for each question type. Our findings provide valuable insight into which combinations of LLMs consistently produce superior results for specific question types. In the four rounds of the 2025 BioASQ challenge, our system achieved notable results: in the Synergy task, we secured 1st place for ideal answers and 2nd place for exact answers in round 2, as well as two shared 1st places for exact answers in round 3 and 4.

The ever-increasing size of language models curtails their widespread access to the community, thereby galvanizing many companies and startups into offering access to large language models through APIs. One particular API, suitable for dense retrieval, is the semantic embedding API that builds vector representations of a given text. With a growing number of APIs at our disposal, in this paper, our goal is to analyze semantic embedding APIs in realistic retrieval scenarios in order to assist practitioners and researchers in finding suitable services according to their needs. Specifically, we wish to investigate the capabilities of existing APIs on domain generalization and multilingual retrieval. For this purpose, we evaluate the embedding APIs on two standard benchmarks, BEIR, and MIRACL. We find that re-ranking BM25 results using the APIs is a budget-friendly approach and is most effective on English, in contrast to the standard practice, i.e., employing them as first-stage retrievers. For non-English retrieval, re-ranking still improves the results, but a hybrid model with BM25 works best albeit at a higher cost. We hope our work lays the groundwork for thoroughly evaluating APIs that are critical in search and more broadly, in information retrieval.

The rapid scaling of Protein Language Models (PLMs) has unlocked unprecedented accuracy in protein structure prediction and design, but the quadratic memory growth of the Key-Value (KV) cache during inference remains a prohibitive barrier for single-GPU deployment and high-throughput generation. While 8-bit quantization is now standard, 3-bit quantization remains elusive due to severe numerical outliers in activations. This paper presents TurboESM, an adaptation of Google's TurboQuant to the PLM domain. We solve the fundamental incompatibility between Rotary Position Embeddings (RoPE) and orthogonal transformations by deriving a RoPE-first rotation pipeline. We introduce a head-wise SVD calibration method tailored to the amino acid activation manifold, a dual look-up table (LUT) strategy for asymmetric K/V distributions, and a 1-bit Quantized Johnson-Lindenstrauss (QJL) residual correction. All experiments are conducted on ESM-2 650M, where our implementation achieves a 7.1x memory reduction (330 MB to 47 MB) while maintaining cosine similarity > 0.96 in autoregressive decoding across diverse protein families, including short peptides, transmembrane helices, enzyme active site fragments, and intrinsically disordered regions. We further implement a Triton-based fused decode attention kernel that eliminates intermediate dequantization memory allocations, achieving a 1.96x speedup over the PyTorch two-step path for the KV fetch operation alone; however, TurboESM incurs a prefill overhead of 21-27 ms relative to the original model due to KV quantization and packing, making it most suitable for memory-bound scenarios rather than latency-critical short-sequence workloads. Analysis reveals that PLMs exhibit sharper outlier profiles than large language models (LLMs) due to amino acid vocabulary sparsity, and our method effectively addresses these distributions.

Protein representation learning is critical for numerous biological tasks. Recently, large transformer-based protein language models (pLMs) pretrained on large scale protein sequences have demonstrated significant success in sequence-based tasks. However, pLMs lack structural context. Conversely, graph neural networks (GNNs) designed to leverage 3D structural information have shown promising generalization in protein-related prediction tasks, but their effectiveness is often constrained by the scarcity of labeled structural data. Recognizing that sequence and structural representations are complementary perspectives of the same protein entity, we propose a multimodal bidirectional hierarchical fusion framework to effectively merge these modalities. Our framework employs attention and gating mechanisms to enable effective interaction between pLMs-generated sequential representations and GNN-extracted structural features, improving information exchange and enhancement across layers of the neural network. This bidirectional and hierarchical (Bi-Hierarchical) fusion approach leverages the strengths of both modalities to capture richer and more comprehensive protein representations. Based on the framework, we further introduce local Bi-Hierarchical Fusion with gating and global Bi-Hierarchical Fusion with multihead self-attention approaches. Our method demonstrates consistent improvements over strong baselines and existing fusion techniques in a variety of protein representation learning benchmarks, including enzyme EC classification, model quality assessment, protein-ligand binding affinity prediction, protein-protein binding site prediction, and B cell epitopes prediction. Our method establishes a new state-of-the-art for multimodal protein representation learning, emphasizing the efficacy of Bi-Hierarchical Fusion in bridging sequence and structural modalities.

Large language models (LLMs) have significantly advanced protein representation learning. However, their capacity to interpret and design antibodies through natural language remains limited. To address this challenge, we present AFD-Instruction, the first large-scale instruction dataset with functional annotations tailored to antibodies. This dataset encompasses two key components: antibody understanding, which infers functional attributes directly from sequences, and antibody design, which enables de novo sequence generation under functional constraints. These components provide explicit sequence-function alignment and support antibody design guided by natural language instructions. Extensive instruction-tuning experiments on general-purpose LLMs demonstrate that AFD-Instruction consistently improves performance across diverse antibody-related tasks. By linking antibody sequences with textual descriptions of function, AFD-Instruction establishes a new foundation for advancing antibody modeling and accelerating therapeutic discovery.

In the field of language modeling, models augmented with retrieval components have emerged as a promising solution to address several challenges faced in the natural language processing (NLP) field, including knowledge grounding, interpretability, and scalability. Despite the primary focus on NLP, we posit that the paradigm of retrieval-enhancement can be extended to a broader spectrum of machine learning (ML) such as computer vision, time series prediction, and computational biology. Therefore, this work introduces a formal framework of this paradigm, Retrieval-Enhanced Machine Learning (REML), by synthesizing the literature in various domains in ML with consistent notations which is missing from the current literature. Also, we found that while a number of studies employ retrieval components to augment their models, there is a lack of integration with foundational Information Retrieval (IR) research. We bridge this gap between the seminal IR research and contemporary REML studies by investigating each component that comprises the REML framework. Ultimately, the goal of this work is to equip researchers across various disciplines with a comprehensive, formally structured framework of retrieval-enhanced models, thereby fostering interdisciplinary future research.

Large pretrained models such as GPT-3 have had tremendous impact on modern natural language processing by leveraging self-supervised learning to learn salient representations that can be used to readily finetune on a wide variety of downstream tasks. We investigate the possibility of transferring such advances to molecular machine learning by building a chemical foundation model, ChemBERTa-2, using the language of SMILES. While labeled data for molecular prediction tasks is typically scarce, libraries of SMILES strings are readily available. In this work, we build upon ChemBERTa by optimizing the pretraining process. We compare multi-task and self-supervised pretraining by varying hyperparameters and pretraining dataset size, up to 77M compounds from PubChem. To our knowledge, the 77M set constitutes one of the largest datasets used for molecular pretraining to date. We find that with these pretraining improvements, we are competitive with existing state-of-the-art architectures on the MoleculeNet benchmark suite. We analyze the degree to which improvements in pretraining translate to improvement on downstream tasks.

Dense retrieval overcome the lexical gap and has shown great success in ad-hoc information retrieval (IR). Despite their success, dense retrievers are expensive to serve across practical use cases. For use cases requiring to search from millions of documents, the dense index becomes bulky and requires high memory usage for storing the index. More recently, learning-to-hash (LTH) techniques, for e.g., BPR and JPQ, produce binary document vectors, thereby reducing the memory requirement to efficiently store the dense index. LTH techniques are supervised and finetune the retriever using a ranking loss. They outperform their counterparts, i.e., traditional out-of-the-box vector compression techniques such as PCA or PQ. A missing piece from prior work is that existing techniques have been evaluated only in-domain, i.e., on a single dataset such as MS MARCO. In our work, we evaluate LTH and vector compression techniques for improving the downstream zero-shot retrieval accuracy of the TAS-B dense retriever while maintaining efficiency at inference. Our results demonstrate that, unlike prior work, LTH strategies when applied naively can underperform the zero-shot TAS-B dense retriever on average by up to 14% nDCG@10 on the BEIR benchmark. To solve this limitation, in our work, we propose an easy yet effective solution of injecting domain adaptation with existing supervised LTH techniques. We experiment with two well-known unsupervised domain adaptation techniques: GenQ and GPL. Our domain adaptation injection technique can improve the downstream zero-shot retrieval effectiveness for both BPR and JPQ variants of the TAS-B model by on average 11.5% and 8.2% nDCG@10 while both maintaining 32times memory efficiency and 14times and 2times speedup respectively in CPU retrieval latency on BEIR. All our code, models, and data are publicly available at https://github.com/thakur-nandan/income.

Motivation: Biomedical question answering often requires evidence beyond topically retrieved literature, including gene alias resolution, database identifier normalization, and atlas-derived biological measurements. However, existing retrieval-augmented generation (RAG) systems typically follow a fixed workflow and lack an explicit mechanism for deciding when retrieved text is sufficient, when curated biomedical knowledge is required, or when executable evidence assembly over structured measurements should be invoked. This motivates a substrate-aware large language model (LLM) harness that selectively assembles sufficient evidence across literature, knowledge bases, and biological atlases. Results: We introduce BioHarness, an LLM harness for staged biomedical evidence assembly across literature retrieval, curated biomedical knowledge resources, and atlas-derived structured measurements. BioHarness first attempts to answer from reranked literature evidence and escalates through grounded cascade control to REPL-style evidence assembly only when the current evidence is uncertain, weakly grounded, or substrate-mismatched. Across 19,302 biomedical QA items spanning seven answer formats, BioHarness improves the pooled score from 65.9 to 71.0 over the strongest non-oracle baseline. Ablations, case studies, and backbone-scaling analyses show that these gains arise from repairing evidence-substrate mismatches through reranking, entity grounding, and structured measurement access, rather than from indiscriminately invoking more reasoning steps, retrieving additional literature, or relying on a particular answer-model scale.

Multi-stage ranking pipelines have been a practical solution in modern search systems, where the first-stage retrieval is to return a subset of candidate documents, and latter stages attempt to re-rank those candidates. Unlike re-ranking stages going through quick technique shifts during past decades, the first-stage retrieval has long been dominated by classical term-based models. Unfortunately, these models suffer from the vocabulary mismatch problem, which may block re-ranking stages from relevant documents at the very beginning. Therefore, it has been a long-term desire to build semantic models for the first-stage retrieval that can achieve high recall efficiently. Recently, we have witnessed an explosive growth of research interests on the first-stage semantic retrieval models. We believe it is the right time to survey current status, learn from existing methods, and gain some insights for future development. In this paper, we describe the current landscape of the first-stage retrieval models under a unified framework to clarify the connection between classical term-based retrieval methods, early semantic retrieval methods and neural semantic retrieval methods. Moreover, we identify some open challenges and envision some future directions, with the hope of inspiring more researches on these important yet less investigated topics.

Retrieval-Augmented Generation (RAG) systems critically depend on retrieval quality, yet no systematic comparison of modern retrieval methods exists for heterogeneous documents containing both text and tabular data. We benchmark ten retrieval strategies spanning sparse, dense, hybrid fusion, cross-encoder reranking, query expansion, index augmentation, and adaptive retrieval on a challenging financial QA benchmark of 23,088 queries over 7,318 documents with mixed text-and-table content. We evaluate retrieval quality via Recall@k, MRR, and nDCG, and end-to-end generation quality via Number Match, with paired bootstrap significance testing. Our results show that (1) a two-stage pipeline combining hybrid retrieval with neural reranking achieves Recall@5 of 0.816 and MRR@3 of 0.605, outperforming all single-stage methods by a large margin; (2) BM25 outperforms state-of-the-art dense retrieval on financial documents, challenging the common assumption that semantic search universally dominates; and (3) query expansion methods (HyDE, multi-query) and adaptive retrieval provide limited benefit for precise numerical queries, while contextual retrieval yields consistent gains. We provide ablation studies on fusion methods and reranker depth, actionable cost-accuracy recommendations, and release our full benchmark code.

Understanding biological processes, drug development, and biotechnological advancements requires detailed analysis of protein structures and sequences, a task in protein research that is inherently complex and time-consuming when performed manually. To streamline this process, we introduce ProteinGPT, a state-of-the-art multi-modal protein chat system, that allows users to upload protein sequences and/or structures for comprehensive protein analysis and responsive inquiries. ProteinGPT seamlessly integrates protein sequence and structure encoders with linear projection layers for precise representation adaptation, coupled with a large language model (LLM) to generate accurate and contextually relevant responses. To train ProteinGPT, we construct a large-scale dataset of 132,092 proteins with annotations, and optimize the instruction-tuning process using GPT-4o. This innovative system ensures accurate alignment between the user-uploaded data and prompts, simplifying protein analysis. Experiments show that ProteinGPT can produce promising responses to proteins and their corresponding questions.

We study the efficiency of multi-vector retrieval methods like ColBERT and its recent variant XTR. We introduce WARP, a retrieval engine that drastically improves the efficiency of XTR-based ColBERT retrievers through three key innovations: (1) WARP_SELECT for dynamic similarity imputation, (2) implicit decompression to bypass costly vector reconstruction, and (3) a two-stage reduction process for efficient scoring. Combined with optimized C++ kernels and specialized inference runtimes, WARP reduces end-to-end latency by 41x compared to XTR's reference implementation and thereby achieves a 3x speedup over PLAID from the the official ColBERT implementation. We study the efficiency of multi-vector retrieval methods like ColBERT and its recent variant XTR. We introduce WARP, a retrieval engine that drastically improves the efficiency of XTR-based ColBERT retrievers through three key innovations: (1) WARP_SELECT for dynamic similarity imputation, (2) implicit decompression during retrieval, and (3) a two-stage reduction process for efficient scoring. Thanks also to highly-optimized C++ kernels and to the adoption of specialized inference runtimes, WARP can reduce end-to-end query latency relative to XTR's reference implementation by 41x. And it thereby achieves a 3x speedup over the official ColBERTv2 PLAID engine, while preserving retrieval quality.

Recent advances in generative modeling show that pretrained representations can improve generation as conditioning features or alignment targets. Motivated by this, we study protein representations for predicting structures beyond conventional function annotation. We propose TriProRep, a structure-aware pretraining method that jointly models three aligned residue-level views: amino-acid identity, backbone geometry, and local full-atom geometry, discretely encoded via VQ-VAE tokenizers. By pretraining to recover original tokens from generator-corrupted views, TriProRep learns to distinguish plausible but incorrect cross-view augmentations from the original protein. We further introduce RepSP, a benchmark for evaluating protein representations in structure-predictive settings. RepSP tests three uses of representations: homodimer co-folding from apo-chain representations, residue-level prediction of homodimer-derived interaction properties, and representation-aligned monomer structure prediction. Across these tasks, TriProRep improves over sequence-only and prior structure-aware representation models, while maintaining competitive performance on conventional benchmarks.

Recently, there has been a significant upsurge of interest in leveraging large language models (LLMs) to assist scientific discovery. However, most LLMs only focus on general science, while they lack domain-specific knowledge, such as chemical molecules and amino acid sequences. To bridge these gaps, we introduce SciDFM, a mixture-of-experts LLM, which is trained from scratch and is able to conduct college-level scientific reasoning and understand molecules and amino acid sequences. We collect a large-scale training corpus containing numerous scientific papers and books from different disciplines as well as data from domain-specific databases. We further fine-tune the pre-trained model on lots of instruction data to improve performances on downstream benchmarks. From experiment results, we show that SciDFM achieves strong performance on general scientific benchmarks such as SciEval and SciQ, and it reaches a SOTA performance on domain-specific benchmarks among models of similar size. We further analyze the expert layers and show that the results of expert selection vary with data from different disciplines. To benefit the broader research community, we open-source SciDFM at https://huggingface.co/OpenDFM/SciDFM-MoE-A5.6B-v1.0.

Understanding the 3D structures of protein multimers is crucial, as they play a vital role in regulating various cellular processes. It has been empirically confirmed that the multimer structure prediction~(MSP) can be well handled in a step-wise assembly fashion using provided dimer structures and predicted protein-protein interactions~(PPIs). However, due to the biological gap in the formation of dimers and larger multimers, directly applying PPI prediction techniques can often cause a poor generalization to the MSP task. To address this challenge, we aim to extend the PPI knowledge to multimers of different scales~(i.e., chain numbers). Specifically, we propose \textsc{PromptMSP}, a pre-training and Prompt tuning framework for Multimer Structure Prediction. First, we tailor the source and target tasks for effective PPI knowledge learning and efficient inference, respectively. We design PPI-inspired prompt learning to narrow the gaps of two task formats and generalize the PPI knowledge to multimers of different scales. We provide a meta-learning strategy to learn a reliable initialization of the prompt model, enabling our prompting framework to effectively adapt to limited data for large-scale multimers. Empirically, we achieve both significant accuracy (RMSD and TM-Score) and efficiency improvements compared to advanced MSP models. The code, data and checkpoints are released at https://github.com/zqgao22/PromptMSP.

Large Language Models (LLMs) have revolutionized the field of natural language processing, but they fall short in comprehending biological sequences such as proteins. To address this challenge, we propose InstructProtein, an innovative LLM that possesses bidirectional generation capabilities in both human and protein languages: (i) taking a protein sequence as input to predict its textual function description and (ii) using natural language to prompt protein sequence generation. To achieve this, we first pre-train an LLM on both protein and natural language corpora, enabling it to comprehend individual languages. Then supervised instruction tuning is employed to facilitate the alignment of these two distinct languages. Herein, we introduce a knowledge graph-based instruction generation framework to construct a high-quality instruction dataset, addressing annotation imbalance and instruction deficits in existing protein-text corpus. In particular, the instructions inherit the structural relations between proteins and function annotations in knowledge graphs, which empowers our model to engage in the causal modeling of protein functions, akin to the chain-of-thought processes in natural languages. Extensive experiments on bidirectional protein-text generation tasks show that InstructProtein outperforms state-of-the-art LLMs by large margins. Moreover, InstructProtein serves as a pioneering step towards text-based protein function prediction and sequence design, effectively bridging the gap between protein and human language understanding.

Motivation: The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein-ligand pairs. On the other hand, large amounts of unlabeled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target specific training. We also compare two decoding strategies to generate compounds: beam search and sampling. Results: The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality. Availability and implementation: The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145

Predicting how cells respond to genetic perturbations is fundamental to understanding gene function, disease mechanisms, and therapeutic development. While recent deep learning approaches have shown promise in modeling single-cell perturbation responses, they struggle to generalize across cell types and perturbation contexts due to limited contextual information during generation. We introduce PT-RAG (Perturbation-aware Two-stage Retrieval-Augmented Generation), a novel framework that extends Retrieval-Augmented Generation beyond traditional language-model applications to cellular biology. Unlike standard RAG systems designed for text retrieval with pre-trained LLMs, perturbation retrieval lacks established similarity metrics and requires learning what constitutes relevant context, making differentiable retrieval essential. PT-RAG addresses this through a two-stage pipeline: first, retrieving candidate perturbations K using GenePT embeddings, then adaptively refining the selection through Gumbel-Softmax discrete sampling conditioned on both the cell state and the input perturbation. This cell-type-aware differentiable retrieval enables end-to-end optimization of the retrieval objective jointly with generation. On the Replogle-Nadig single-gene perturbation dataset, we demonstrate that PT-RAG outperforms both STATE and vanilla RAG under identical experimental conditions, with the strongest gains in distributional similarity metrics (W_1, W_2). Notably, vanilla RAG's dramatic failure is itself a key finding: it demonstrates that differentiable, cell-type-aware retrieval is essential in this domain, and that naive retrieval can actively harm performance. Our results establish retrieval-augmented generation as a promising paradigm for modelling cellular responses to gene perturbation. The code to reproduce our experiments is available at https://github.com/difra100/PT-RAG_ICLR.

Neural information retrieval (IR) has greatly advanced search and other knowledge-intensive language tasks. While many neural IR methods encode queries and documents into single-vector representations, late interaction models produce multi-vector representations at the granularity of each token and decompose relevance modeling into scalable token-level computations. This decomposition has been shown to make late interaction more effective, but it inflates the space footprint of these models by an order of magnitude. In this work, we introduce ColBERTv2, a retriever that couples an aggressive residual compression mechanism with a denoised supervision strategy to simultaneously improve the quality and space footprint of late interaction. We evaluate ColBERTv2 across a wide range of benchmarks, establishing state-of-the-art quality within and outside the training domain while reducing the space footprint of late interaction models by 6--10times.

Effective biomedical information retrieval requires modeling domain semantics and hierarchical relationships among biomedical texts. Existing biomedical generative retrievers build on coarse binary relevance signals, limiting their ability to capture semantic overlap. We propose BioHiCL (Biomedical Retrieval with Hierarchical Multi-Label Contrastive Learning), which leverages hierarchical MeSH annotations to provide structured supervision for multi-label contrastive learning. Our models, BioHiCL-Base (0.1B) and BioHiCL-Large (0.3B), achieve promising performance on biomedical retrieval, sentence similarity, and question answering tasks, while remaining computationally efficient for deployment.

In this work, we propose a simple method that applies a large language model (LLM) to large-scale retrieval in zero-shot scenarios. Our method, the Language language model as Retriever (LameR), is built upon no other neural models but an LLM, while breaking brute-force combinations of retrievers with LLMs and lifting the performance of zero-shot retrieval to be very competitive on benchmark datasets. Essentially, we propose to augment a query with its potential answers by prompting LLMs with a composition of the query and the query's in-domain candidates. The candidates, regardless of correct or wrong, are obtained by a vanilla retrieval procedure on the target collection. As a part of the prompts, they are likely to help LLM generate more precise answers by pattern imitation or candidate summarization. Even if all the candidates are wrong, the prompts at least make LLM aware of in-collection patterns and genres. Moreover, due to the low performance of a self-supervised retriever, the LLM-based query augmentation becomes less effective as the retriever bottlenecks the whole pipeline. Therefore, we propose to leverage a non-parametric lexicon-based method (e.g., BM25) as the retrieval module to capture query-document overlap in a literal fashion. As such, LameR makes the retrieval procedure transparent to the LLM, thus circumventing the performance bottleneck.

Recent research trends in computational biology have increasingly focused on integrating text and bio-entity modeling, especially in the context of molecules and proteins. However, previous efforts like BioT5 faced challenges in generalizing across diverse tasks and lacked a nuanced understanding of molecular structures, particularly in their textual representations (e.g., IUPAC). This paper introduces BioT5+, an extension of the BioT5 framework, tailored to enhance biological research and drug discovery. BioT5+ incorporates several novel features: integration of IUPAC names for molecular understanding, inclusion of extensive bio-text and molecule data from sources like bioRxiv and PubChem, the multi-task instruction tuning for generality across tasks, and a novel numerical tokenization technique for improved processing of numerical data. These enhancements allow BioT5+ to bridge the gap between molecular representations and their textual descriptions, providing a more holistic understanding of biological entities, and largely improving the grounded reasoning of bio-text and bio-sequences. The model is pre-trained and fine-tuned with a large number of experiments, including 3 types of problems (classification, regression, generation), 15 kinds of tasks, and 21 total benchmark datasets, demonstrating the remarkable performance and state-of-the-art results in most cases. BioT5+ stands out for its ability to capture intricate relationships in biological data, thereby contributing significantly to bioinformatics and computational biology. Our code is available at https://github.com/QizhiPei/BioT5.

A key component of fact verification is thevevidence retrieval, often from multiple documents. Recent approaches use dense representations and condition the retrieval of each document on the previously retrieved ones. The latter step is performed over all the documents in the collection, requiring storing their dense representations in an index, thus incurring a high memory footprint. An alternative paradigm is retrieve-and-rerank, where documents are retrieved using methods such as BM25, their sentences are reranked, and further documents are retrieved conditioned on these sentences, reducing the memory requirements. However, such approaches can be brittle as they rely on heuristics and assume hyperlinks between documents. We propose a novel retrieve-and-rerank method for multi-hop retrieval, that consists of a retriever that jointly scores documents in the knowledge source and sentences from previously retrieved documents using an autoregressive formulation and is guided by a proof system based on natural logic that dynamically terminates the retrieval process if the evidence is deemed sufficient. This method is competitive with current state-of-the-art methods on FEVER, HoVer and FEVEROUS-S, while using 5 to 10 times less memory than competing systems. Evaluation on an adversarial dataset indicates improved stability of our approach compared to commonly deployed threshold-based methods. Finally, the proof system helps humans predict model decisions correctly more often than using the evidence alone.