Structured Inference with Large Language Gibbs

Abstract: The knowledge encoded in large language models (LLMs) can serve as a substrate for structured reasoning over variables describing a complex world, but accessing this knowledge in a probabilistically coherent manner poses a difficult inference problem. We propose Large Language Gibbs, a scheme for structured probabilistic inference that uses conditional distributions of an LLM as transition operators. Rather than sampling structured objects through single-pass autoregressive generation, we iteratively resample individual variables conditioned on others using an LLM's next-token conditionals. This approach avoids order-dependent biases and produces a stationary distribution that reflects a compromise between all local conditionals. We apply this approach to sampling from synthetic distributions, consistent reasoning tasks, and Bayesian structure learning. The results suggest that the use of LLM conditionals in MCMC is a practical alternative to one-pass generation for structured probabilistic inference under a world prior accessible through noisy LLM conditionals.

Sanghyeok Choi
Henry Gouk
Esmeralda S. Whitammer


Circuit Tracing in Autoregressive Protein Language Models

Abstract: Protein language models (pLMs) can generate novel protein sequences with properties beyond those observed in nature, yet the mechanisms underlying protein generation remain poorly understood. Existing mechanistic interpretability methods based on sparse autoencoders and transcoders primarily focus on protein representation learning models and do not capture the computation required for autoregressive generation. Here, we introduce ProGenMech, a mechanistic interpretability framework for generative protein language models that extends cross-layer transcoders (CLTs) to ProGen3, a sparse Mixture-of-Experts model trained for both causal generation and span infilling. Unlike per-layer approaches, CLTs reconstruct each layer using sparse latent variables from all preceding layers, enabling faithful recovery of inter-layer generative computation. We further develop a zero-shot circuit discovery framework to identify sparse latent circuits responsible for protein generation and fitness prediction. In causal generation and zero-shot fitness estimation tasks, ProGenMech outperforms local transcoder baselines in recovering ProGen3's probability distribution and functional scoring behavior, while matching the original model's generative distribution in span infilling tasks. Moreover, the recovered circuits reveal biologically meaningful motifs and functional regions associated with conserved sequence patterns and protein fitness landscapes, establishing a foundation for interpretable and steerable protein generation.

Darin Tsui
William Deinzer
Daniel Saeedi
Amirali Aghazadeh


Viral Proteins Reveal Geometry of Protein Language Models

Abstract: Protein language models are trained on highly imbalanced datasets, raising the question of how they represent underrepresented biological sequences. Using viral proteins as a case study across ESM model families, we identify a dominant nativeness axis in embedding space, aligned with masked reconstruction perplexity, that orders sequences from well-modeled cellular proteins through viral proteins to shuffled and random sequences. Scaling contracts this axis unevenly across viral families. Despite this, protein language model embeddings retain viral-specific signal: viral proteins remain linearly separable beyond zero-shot perplexity and shallow sequence features. Together, these results suggest that pLM representations are structured by a general notion of nativeness while preserving information specific to distinct biological groups.

Arthur Bigot
Harmon Bhasin
Core Francisco Park
Eugene Shakhnovich
Dianzhuo Wang


Interpretable enzyme function prediction via sparse autoencoder features of ESMC across the microbial protein universe

Abstract: Microbial genomes and metagenomes contain millions of proteins whose enzymatic functions remain unknown, the enzyme dark matter. While deep learning has improved protein function prediction, most methods are black boxes relying on sequence or structural similarity, limiting discovery of novel catalytic activities. The ESMC-6B protein language model and its sparse autoencoder with a 16,384-dimensional codebook of interpretable biological concepts, each annotated by GPT-5, creates a new opportunity: using these features directly as semantic signatures for enzyme function. Here, we show that ESMC-SAE features enable accurate and interpretable enzyme commission (EC) number prediction without task-specific training or GPU-intensive computation. On a balanced benchmark of 4,868 microbial SwissProt enzymes across 161 EC3 subclasses, ESMC-SAE binary features achieve 78.9% top-1 and 88.5% top-5 accuracy, 37.6% higher than 3-mer baselines (57.3%). In leave-one-EC3-class-out evaluation simulating discovery of novel enzyme classes, SAE features recover the EC1 superclass in 47.7% of cases (3.3x random, 14.3%), versus 26.6% for sequence methods. Discriminative features correspond to mechanistically interpretable concepts: catalytic triad geometry for hydrolases, NAD(P)H-binding Rossmann folds for oxidoreductases, phosphate-binding P-loops for transferases. We also survey the ESM Atlas of 7.7 million clusters and identify 169,859 dark enzyme-like candidates across all major microbial phyla. Our results establish a paradigm for enzyme function discovery in microbial dark matter: interpretable by design, scalable without GPU clusters, and applicable to the billions of proteins in the ESM Atlas.

Yue Hu
Wanyu Cheng
Junqing Wang
Yingchao Liu


The Dynamics of Human and AI-Generated Language: How Semantics Fluctuates across Different Timescales

Abstract: Spoken language, whether produced by humans or large language models (LLM), unfolds over time with varying semantic content. However, we still lack simple, interpretable time-series features that capture how generic versus specific content is distributed over time, and that can be used to compare human and AI-generated speech. We introduce a semantic-timescale analysis pipeline that turns word-level transcripts with timestamps into semantic time-series. For each spoken narrative, we compute (i) semantic specificity using WordNet-based word depth and (ii) contextual similarity using SBERT embeddings and quantify their temporal dependence using autocorrelation-window measures (ACW-0 and related metrics). We then compare original speech to multiple shuffled controls that selectively disrupt lexical identity, temporal order, and word duration. Across human-read autobiographical narratives, TTS readings, and LLM-generated texts rendered with TTS, we find that segments with longer ACW-0 in the semantic time-series tend to contain more generic vocabulary, whereas segments with shorter ACW-0 are enriched in more specific words. These associations are strongly attenuated or abolished when word order and timing are randomized, indicating that ACW-based measures capture non-trivial temporal organization of semantic content beyond static lexical distributions. Our results suggest that ACW-based semantic timescales are a useful family of features for analyzing and comparing the temporal structure of human and AI-generated speech.

Han-Jen Chang
Yasir Çatal
Angelika Wolman
Agustín Ibáñez
David Smith
I-Wen Su
Kai-Yuan Cheng
Georg Northoff

Computer Speech & Language (2026) 102013


Protein Dynamics Beyond Structure Prediction

Abstract: The ability to predict protein three-dimensional structures from amino acid sequences is a landmark achievement in molecular biology, where recent deep learning approaches such as AlphaFold are the culmination of decades of work. Yet, the quantitative understanding of how protein sequences give rise to dynamic conformational changes and higher-order assemblies remains unsolved. Folding and conformational states are dynamic, stochastic processes, shaped by sequence, energy, co-translational constraints, chaperone machineries, and the physicochemical conditions of the cellular environment. Recent advances now position the field to move beyond static structural endpoints toward a mechanistic understanding of folding dynamics in living systems. Single-molecule techniques enable time-resolved observation of folding trajectories and intermediate states hitherto hidden by traditional structural biology approaches, while computational innovations and data-driven approaches offer new ways to integrate heterogeneous data across scales. In this Roadmap, we review the current conceptual landscape of protein folding, examine the experimental and theoretical gaps that remain, and discuss emerging strategies that integrate high-resolution measurements with multiscale modeling. We outline a roadmap toward a quantitative and predictive science of protein folding dynamics, conformational kinetics, and macromolecular self-assembly. Realizing this vision would transform our understanding of the dynamics of molecular self-organization, from the folding of individual polypeptides to the emergence of dynamic macromolecular complexes. This will enable rational control of folding and misfolding in health and disease, extend protein engineering principles beyond static structural design, and establish a mechanistic foundation for predictive and personalized interventions in proteostasis-related disorders.

Juliette Griffié
Sviatlana Shashkova
Antonio Ciarlo
Sreekanth K. Manikandan
Claes Andréasson
Malin Bäckström
Tristan Bereau
Hjalmar Brismar
Carlos Bustamante
Marta Carroni
Roberto Covino
Andreas Dahlin
Sebastian Deindl
Lucie Delemotte
Arne Elofsson
John Eriksson
Giovanna Fragneto
Anders Gunnarsson
Per Hammarström
Caroline Ingre
Christian Kaiser
Petronella Kettunen
Mark C. Leake
Benjamin Loos
Anna Månberg
Antonia S. J. S. Mey
Richard Neutze
Thomas Nyström
Karl Palmås
Charley Schaefer
Markus J. Tamás
Nicola Ticozzi
Tomás S. Pilvelic
Jacopo Sacquegno
B. M.
Tijms
Gunnar von Heijne
Björn Wallner
Vitali Zhaunerchyk
Simon Olsson
Joana B. Pereira
Julia Fernandez-Rodriguez
Fredrik Westerlund
Giovanni Volpe


AF_Cache: Efficient Pipeline for Running AlphaFold for High-Throughput Protein-Protein Interaction Prediction

Abstract: Motivation: Accurate prediction of protein-protein interactions is essential for understanding biological processes, and recent advances such as AlphaFold2 and AlphaFold3 have enabled structure-based interaction prediction at unprecedented accuracy. However, the high computational cost of these methods, driven primarily by CPU-based repeated multiple sequence alignment (MSA) generation and, for AlphaFold2, repeated model recompilations, limits their applicability in large-scale, high-throughput settings. This creates a need for efficient pipelines that retain predictive performance while substantially reducing runtime. Results: We present AF_Cache, a high-throughput Nextflow pipeline for accelerating protein-protein interaction prediction using AlphaFold2 and AlphaFold3. AF_Cache combines GPU-accelerated MSA generation with MMseqs2, feature caching to eliminate redundant alignment computations, and sequence length bucketing to minimise repeated JAX compilations. Benchmarking on a dataset of 5,050 human mitochondrial protein pairs demonstrates a $\sim$2-fold reduction in inference time for AlphaFold2 and up to a 13-fold speedup of the MSA generation. AF\_Cache enables efficient large-scale interaction screening and provides a practical framework for deploying AlphaFold-based methods in high-throughput applications. Availability and implementation: The code and Nextflow pipeline are available on GitHub here: https://github.com/clami66/AF_cache. The code for reproducing the results of the paper, the MSAs, and the predicted models can be found at Zenodo: https://zenodo.org/records/20478892

Sarah Narrowe
Arne Elofsson Claudio Mirabello


Structure-Aware Prediction of PROTAC-Mediated Protein Degradability via Graph Neural Networks

Abstract: Proteolysis-targeting chimeras (PROTACs) can selectively degrade disease-causing proteins, yet predicting which targets are amenable to degradation remains a critical bottleneck: existing computational methods require the complete PROTAC molecular structure, information unavailable before synthesis. We present DegradoMap, a graph neural network that predicts PROTAC-mediated degradability from protein structure and E3 ligase identity alone -- the minimal information available at the target selection stage. The model encodes biophysical priors through lysine-weighted graph pooling with per-protein normalization, models protein-E3 compatibility via cross-attention, and integrates cellular context from the Cancer Dependency Map. On the PROTAC-8K benchmark (3,101 samples, 155 targets, 10 E3 ligases), DegradoMap achieves 0.646+-0.124 AUROC on target-unseen evaluation (best seed: 0.7449) and 0.811 AUROC on CRBN->VHL E3-unseen transfer, outperforming GNN and machine learning baselines. The model additionally recommends optimal E3 ligases with 74% Hit@3 accuracy. Two findings carry broader implications: E(3)-equivariant architectures underperform the simpler invariant design for this scalar prediction task, and ESM-2 embeddings improve peak performance only with careful regularization -- naive integration fails. DegradoMap provides pre-synthesis computational guidance for degradability assessment; its well-calibrated confidence scores (ECE = 0.029, target-unseen) enable practitioners to prioritize high-confidence predictions for experimental follow-up. However, the high seed variance (std = 0.124) and limited E3 coverage require ensembling for reliable deployment.


Structure-Guided Adaptive Propagation for Protein-Protein Interaction Site Prediction

Abstract: Accurate prediction of protein-protein interaction sites (PPIS) is essential for understanding cellular processes, disease mechanisms, and therapeutic target discovery. Graph-based deep learning has advanced PPIS prediction by incorporating residue-level structural context. However, most graph-based models still rely on fixed propagation schemes that treat all residues similarly, despite the structural and functional heterogeneity of protein interfaces. Such propagation may limit the ability to adapt information diffusion to local geometric environments, making it difficult to distinguish true interaction sites from structurally similar non-interacting neighbors. We present SGAP-PPIS, a structure-guided adaptive propagation model for PPIS prediction. Rather than using a fixed propagation mechanism, SGAP-PPIS leverages multi-scale geometric states from an equivariant graph neural network to generate residue-wise propagation coefficients. This design allows each residue to adaptively balance local feature preservation and neighborhood diffusion according to its geometric microenvironment. Experimental results show that SGAP-PPIS achieves competitive performance among the state-of-the-art methods on Test\_60. Ablation studies show that geometry-conditioned adaptive propagation, scale-aligned geometric guidance, and multi-step propagation-state representation jointly drive these improvements.

Enqiang Zhu
Yizi Liu
Yilong Luo
Yao Chen
Yu Zhang
Baoshan Ma


AMix-2: Establishing Protein as a Native Modality in Large Language Models

Abstract: 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.

Keyue Qiu
Yixin Wu
Lihao Wang
Yawen Ouyang
Jixiang Yu
Zihan Zhou
Changze Lv
Dongyu Xue
Yuxuan Song
Xinbo Zhang
Hao Wang
Jiangtao Feng
Zhiqiang Gao
Lijun Wu
Xiaoqing Zheng
Ka-Chun Wong
Lei Bai
Ya-Qin Zhang
Wei-Ying Ma
Dahua Lin
Bowen Zhou
Hao Zhou


Atom-level Protein Representation Learning Improves Protein Structure Prediction

Abstract: 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.

Taewon Kim
Hyosoon Jang
Hyunjin Seo
Seonghwan Seo
Hyeongwoo Kim
Wonho Zhung
Mingyeong Shin
Wooyoun Kim
Sungsoo Ahn


Structural Interpretations of Protein Language Model Representations via Differentiable Graph Partitioning

Abstract: Protein language models such as ESM-2 learn rich residue representations that achieve strong performance on protein function prediction, but their features remain difficult to interpret as structural $\&$ evolutionary signals are encoded in dense latent spaces. We propose a plug-$\&$-play framework that projects ESM-2 representations onto protein contact graphs $\&$ applies $\textbf{SoftBlobGIN}$, a lightweight Graph Isomorphism Network with differentiable Gumbel-softmax substructure pooling, to perform structure-aware message passing $\&$ learn coarse functional substructures for downstream prediction tasks. Across enzyme classification, SoftBlobGIN achieves 92.8\% accuracy $\&$ 0.898 macro-F1. Unlike post hoc analysis of protein language models alone, our method produces directly auditable structural explanations: GNNExplainer recovers biologically meaningful active-site residues, spatially localized functional clusters, $\&$ catalytic contact patterns. On binding-site detection, SoftBlobGIN improves residue AUROC from $0.885$ using an ESM-2 linear probe to $0.983$, indicating that these structural explanations are not recoverable from language-model features alone. Learned blob partitions provide an additional layer of interpretability by automatically grouping residues into functional substructures, with blobs containing annotated active-site residues showing $1.85\times$ higher importance than other blobs ($ρ{=}0.339$, $p{=}0.009$), without any active-site supervision. Our framework requires no retraining of the language model, adds only $\sim$1.1M parameters, $\&$ generalises across ProteinShake tasks, achieving $F_{\max}$ of $0.733$ on Gene Ontology prediction $\&$ AUROC of $0.969$ on binding-site detection. We position this as an interpretable structural companion to protein language models that makes their predictions more transparent $\&$ auditable.

Siddhant Dutta
Edward Tan Beng Wai
Soumick Sarker
Pasan Gunawardane
Jagath C. Rajapakse


ProteinJEPA: Latent prediction complements protein language models

Abstract: 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, \b{eta}β\b{eta}-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.


ProtSent: Protein Sentence Transformers

Abstract: 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.

Dan Ofer
Oriel Perets
Michal Linial
Nadav Rappoport


Better Protein Function Prediction by Modeling Survivorship Bias

Abstract: Protein sequence data from nature exhibits survivorship bias: we only observe data from those organisms that survive and reproduce, while non-functional protein mutations are eliminated by natural selection. Thus, predicting whether a protein sequence is functional often requires learning from positive examples alone. While positive-unlabeled (PU) learning frameworks offer a generic solution to this problem, existing PU methods ignore the evolutionary processes that shape sequence observability and cause survivorship bias. Consider a sequence that is one mutation away from a commonly-observed protein variant in a well-surveilled organism. If the sequence were functional, it would likely be observed. If it is not observed, this suggests non-functionality. In contrast, sequences that are unlikely to arise through mutation may be missing simply because they never arose. Thus, these two kinds of missing sequences should be treated differently when training models. In this work, we propose Evo-PU, a PU learning framework that uses a scientific understanding of nucleotide mutation to model survivorship bias for well-surveilled single-organism sequence data. On three prediction tasks using single-organism uniform-coverage surveillance data -- predicting results from held-out influenza and respiratory syncytial virus (RSV) mutagenesis studies, and predicting future SARS-CoV-2 variants -- Evo-PU outperforms standard PU learning, one-class classification (OCC), and protein language models (PLMs). On prediction tasks from multi-organism ProteinGym datasets with more heterogeneous surveillance coverage, we identify opportunities to generalize our approach.

Zhongmou Chao
Poompol Buathong
Ekaterina Selivanovitch
Susan Daniel
Peter I. Frazier


Targeted Linguistic Analysis of Sign Language Models with Minimal Translation Pairs

Abstract: Models of sign language have historically lagged behind those for spoken language (text and speech). Recent work has greatly improved their performance on tasks like sign language translation and isolated sign recognition. However, it remains unclear to what extent existing models capture various linguistic phenomena of sign language, and how well they use cues from the multiple articulators used in sign language (hands, upper body, face). We introduce a new benchmark dataset for American Sign Language, ASL Minimal Translation Pairs (ASL-MTP), divided into multiple types of sign language phenomena and corresponding minimal pairs of translations, for performing such linguistic analyses. As a case study, we use ASL-MTP to analyze a state-of-the-art ASL-to-English translation model. We conduct a targeted analysis of the model by ablating various input cues during training and inference and evaluating on the phenomena in ASL-MTP. Our results show that, while the model performs above chance level on most of the phenomena, it relies strongly on manual cues while often missing crucial non-manual cues.

Serpil Karabüklü
Kanishka Misra
Shester Gueuwou
Diane Brentari
Greg Shakhnarovich
Karen Livescu


TriFit: Trimodal Fusion with Protein Dynamics for Mutation Fitness Prediction

Abstract: Predicting the functional impact of single amino acid substitutions (SAVs) is central to understanding genetic disease and engineering therapeutic proteins. While protein language models and structure-based methods have achieved strong performance on this task, they systematically neglect protein dynamics; residue flexibility, correlated motions, and allosteric coupling are well-established determinants of mutational tolerance in structural biology, yet have not been incorporated into supervised variant effect predictors. We present TriFit, a multimodal framework that integrates sequence, structure, and protein dynamics through a four-expert Mixture-of-Experts (MoE) fusion module with trimodal cross-modal contrastive learning. Sequence embeddings are extracted via masked marginal scoring with ESM-2 (650M); structural embeddings from AlphaFold2-predicted C-alpha geometries; and dynamics embeddings from Gaussian Network Model (GNM) B-factors, mode shapes, and residue-residue cross-correlations. The MoE router adaptively weights modality combinations conditioned on the input, enabling protein-specific fusion without fixed modality assumptions. On the ProteinGym substitution benchmark (217 DMS assays, 696k SAVs), TriFit achieves AUROC 0.897 +/- 0.0002, outperforming all supervised baselines including Kermut (0.864) and ProteinNPT (0.844), and the best zero-shot model ESM3 (0.769). Ablation studies confirm that dynamics provides the largest marginal contribution over pairwise modality combinations, and TriFit achieves well-calibrated probabilistic outputs (ECE = 0.044) without post-hoc correction.


Rethinking Token Prediction: Tree-Structured Diffusion Language Model

Abstract: Discrete diffusion language models have emerged as a competitive alternative to auto-regressive language models, but training them efficiently under limited parameter and memory budgets remains challenging. Modern architectures are predominantly based on a full-vocabulary token prediction layer, which accounts for a substantial fraction of model parameters (e.g., more than 20% in small scale DiT-style designs) and often dominates peak GPU memory usage. This leads to inefficient use of both parameters and memory under constrained training resources. To address this issue, we revisit the necessity of explicit full-vocabulary prediction, and instead exploit the inherent structure among tokens to build a tree-structured diffusion language model. Specifically, we model the diffusion process with intermediate latent states corresponding to a token's ancestor nodes in a pre-constructed vocabulary tree. This tree-structured factorization exponentially reduces the classification dimensionality, makes the prediction head negligible in size, and enables reallocation of parameters to deepen the attention blocks. Empirically, under the same parameter budget, our method reduces peak GPU memory usage by half while matching the perplexity performance of state-of-the-art discrete diffusion language models.

Zihao Wu
Haoming Yang
Juncheng Dong
Vahid Tarokh


Sampling at intermediate temperatures is optimal for training large language models in protein structure prediction

Abstract: We investigate the parameter space of transformer models trained on protein sequence data using a statistical mechanics framework, sampling the loss landscape at varying temperatures by Langevin dynamics to characterize the low-loss manifold and understand the mechanisms underlying the superior performance of transformers in protein structure prediction. We find that, at variance with feedforward networks, the lack of a first--order--like transition in the loss of the transformer produces a range of intermediate temperatures with good learning properties. We show that the parameters of most layers are highly conserved at these temperatures if the dimension of the embedding is optimal, and we provide an operative way to find this dimension. Finally, we show that the attention matrix is more predictive of the contact maps of the protein at higher temperatures and for higher dimensions of the embedding than those optimal for learning.


Merge and Conquer: Instructing Multilingual Models by Adding Target Language Weights

Abstract: Large Language Models (LLMs) remain heavily centered on English, with limited performance in low-resource languages. Existing adaptation approaches, such as continual pre-training, demand significant computational resources. In the case of instructed models, high-quality instruction data is also required, both of which are often inaccessible for low-resource language communities. Under these constraints, model merging offers a lightweight alternative, but its potential in low-resource contexts has not been systematically explored. In this work, we explore whether it is possible to transfer language knowledge to an instruction-tuned LLM by merging it with a language-specific base model, thereby eliminating the need of language-specific instructions and repeated fine-tuning processes whenever stronger instructed variants become available. Through experiments covering four Iberian languages (Basque, Catalan, Galician, and Spanish) and two model families, we show that merging enables effective instruction following behavior in new languages and even supports multilingual capability through the combination of multiple language-specific models. Our results indicate that model merging is a viable and efficient alternative to traditional adaptation methods for low-resource languages, achieving competitive performance while greatly reducing computational cost.

Eneko Valero
Maria Ribalta i Albado
Oscar Sainz
Naiara Perez
German Rigau


Introducing MELI: the Mandarin-English Language Interview Corpus

Abstract: We introduce the Mandarin-English Language Interview (MELI) Corpus, an open-source resource of 29.8 hours of speech from 51 Mandarin-English bilingual speakers. MELI combines matched sessions in Mandarin and English with two speaking styles: read sentences and spontaneous interviews about language varieties, standardness, and learning experiences. Audio was recorded at 44.1 kHz (16-bit, stereo). Interviews were fully transcribed, force-aligned at word and phone levels, and anonymized. Descriptively, the Mandarin component totals ~14.7 hours (mean duration 17.3 minutes) and the English component ~15.1 hours (mean duration 17.8 minutes). We report token/type statistics for each language and document code-switching patterns (frequent in Mandarin sessions; more limited in English sessions). The corpus design supports within-/cross-speaker, within/cross-language acoustic comparison and links acoustics to speakers' stated language attitudes, enabling both quantitative and qualitative analyses. The MELI Corpus will be released with transcriptions, alignments, metadata, scans of labelled maps and documentation under a CC BY-NC 4.0 license.


Central Dogma Transformer III: Interpretable AI Across DNA, RNA, and Protein

Abstract: Biological AI models increasingly predict complex cellular responses, yet their learned representations remain disconnected from the molecular processes they aim to capture. We present CDT-III, which extends mechanism-oriented AI across the full central dogma: DNA, RNA, and protein. Its two-stage Virtual Cell Embedder architecture mirrors the spatial compartmentalization of the cell: VCE-N models transcription in the nucleus and VCE-C models translation in the cytosol. On five held-out genes, CDT-III achieves per-gene RNA r=0.843 and protein r=0.969. Adding protein prediction improves RNA performance (r=0.804 to 0.843), demonstrating that downstream tasks regularize upstream representations. Protein supervision sharpens DNA-level interpretability, increasing CTCF enrichment by 30%. Analysis of experimentally measured mRNA and protein responses reveals that the majority of genes with observable mRNA changes show opposite protein-level changes (66.7% at |log2FC|>0.01, rising to 87.5% at |log2FC|>0.02), exposing a fundamental limitation of RNA-only perturbation models. Despite this pervasive direction discordance, CDT-III correctly predicts both mRNA and protein responses. Applied to in silico CD52 knockdown approximating Alemtuzumab, the model predicts 29/29 protein changes correctly and rediscovers 5 of 7 known clinical side effects without clinical data. Gradient-based side effect profiling requires only unperturbed baseline data (r=0.939), enabling screening of all 2,361 genes without new experiments.


Task-Specific Efficiency Analysis: When Small Language Models Outperform Large Language Models

Abstract: Large Language Models achieve remarkable performance but incur substantial computational costs unsuitable for resource-constrained deployments. This paper presents the first comprehensive task-specific efficiency analysis comparing 16 language models across five diverse NLP tasks. We introduce the Performance-Efficiency Ratio (PER), a novel metric integrating accuracy, throughput, memory, and latency through geometric mean normalization. Our systematic evaluation reveals that small models (0.5--3B parameters) achieve superior PER scores across all given tasks. These findings establish quantitative foundations for deploying small models in production environments prioritizing inference efficiency over marginal accuracy gains.

Jinghan Cao
Yu Ma
Xinjin Li
Qingyang Ren
Xiangyun Chen

The European Symposium on Artificial Neural Networks


Cross-Granularity Representations for Biological Sequences: Insights from ESM and BiGCARP

Abstract: Recent advances in general-purpose foundation models have stimulated the development of large biological sequence models. While natural language shows symbolic granularity (characters, words, sentences), biological sequences exhibit hierarchical granularity whose levels (nucleotides, amino acids, protein domains, genes) further encode biologically functional information. In this paper, we investigate the integration of cross-granularity knowledge from models through a case study of BiGCARP, a Pfam domain-level model for biosynthetic gene clusters, and ESM, an amino acid-level protein language model. Using representation analysis tools and a set of probe tasks, we first explain why a straightforward cross-model embedding initialization fails to improve downstream performance in BiGCARP, and show that deeper-layer embeddings capture a more contextual and faithful representation of the model's learned knowledge. Furthermore, we demonstrate that representations at different granularities encode complementary biological knowledge, and that combining them yields measurable performance gains in intermediate-level prediction tasks. Our findings highlight cross-granularity integration as a promising strategy for improving both the performance and interpretability of biological foundation models.

Hanlin Xiao
Rainer Breitling
Eriko Takano
Mauricio A. Álvarez

IEEE International Conference on Bioinformatics and Biomedicine


From Snapshots to Symphonies: The Evolution of Protein Prediction from Static Structures to Generative Dynamics and Multimodal Interactions

Abstract: The protein folding problem has been fundamentally transformed by artificial intelligence, evolving from static structure prediction toward the modeling of dynamic conformational ensembles and complex biomolecular interactions. This review systematically examines the paradigm shift in AI driven protein science across five interconnected dimensions: unified multimodal representations that integrate sequences, geometries, and textual knowledge; refinement of static prediction through MSA free architectures and all atom complex modeling; generative frameworks, including diffusion models and flow matching, that capture conformational distributions consistent with thermodynamic ensembles; prediction of heterogeneous interactions spanning protein ligand, protein nucleic acid, and protein protein complexes; and functional inference of fitness landscapes, mutational effects, and text guided property prediction. We critically analyze current bottlenecks, including data distribution biases, limited mechanistic interpretability, and the disconnect between geometric metrics and biophysical reality, while identifying future directions toward physically consistent generative models, multimodal foundation architectures, and experimental closed loop systems. This methodological transformation marks artificial intelligence's transition from a structural analysis tool into a universal simulator capable of understanding and ultimately rewriting the dynamic language of life.


Integrative modelling of protein-glycan interactions with HADDOCK3

Abstract: Glycans are structurally diverse and flexible biomolecules that play key roles in many biological processes. Their conformational variability makes the modeling of their interactions with proteins particularly challenging. This chapter presents a step-by-step protocol for modeling protein-glycan interactions using HADDOCK3, an integrative modeling platform that supports the inclusion of experimental or predicted interaction restraints and allows for flexible refinement of the solutions. The workflow is illustrated using the interaction between a linear homopolymer glycan, 4-beta-glucopyranose, and the catalytic domain of the Humicola grisea Cel12A enzyme, for which an experimental X-ray structure is available as a reference. Detailed instructions are provided for input structure preparation, restraint definition, docking setup, execution, and result analysis. Application of the protocol starting from unbound structures yields models of acceptable to medium quality, with interface-ligand RMSD values below 3 angstroms. Although illustrated on a specific system, the protocol has been optimized and benchmarked on multiple protein-glycan complexes and is broadly applicable to similar systems, providing a framework for integrative modeling of protein-glycan interactions.

Victor Reys
Marco Giulini
Alexandre M. J. J. Bonvin


Robust Language Identification for Romansh Varieties

Abstract: The Romansh language has several regional varieties, called idioms, which sometimes have limited mutual intelligibility. Despite this linguistic diversity, there has been a lack of documented efforts to build a language identification (LID) system that can distinguish between these idioms. Since Romansh LID should also be able to recognize Rumantsch Grischun, a supra-regional variety that combines elements of several idioms, this makes for a novel and interesting classification problem. In this paper, we present a LID system for Romansh idioms based on an SVM approach. We evaluate our model on a newly curated benchmark across two domains and find that it reaches an average in-domain accuracy of 97%, enabling applications such as idiom-aware spell checking or machine translation. Our classifier is publicly available.

Charlotte Model
Sina Ahmadi
Jannis Vamvas


Reverse Distillation: Consistently Scaling Protein Language Model Representations

Abstract: Unlike the predictable scaling laws in natural language processing and computer vision, protein language models (PLMs) scale poorly: for many tasks, models within the same family plateau or even decrease in performance, with mid-sized models often outperforming the largest in the family. We introduce Reverse Distillation, a principled framework that decomposes large PLM representations into orthogonal subspaces guided by smaller models of the same family. The resulting embeddings have a nested, Matryoshka-style structure: the first k dimensions of a larger model's embedding are exactly the representation from the smaller model. This ensures that larger reverse-distilled models consistently outperform smaller ones. A motivating intuition is that smaller models, constrained by capacity, preferentially encode broadly-shared protein features. Reverse distillation isolates these shared features and orthogonally extracts additional contributions from larger models, preventing interference between the two. On ProteinGym benchmarks, reverse-distilled ESM-2 variants outperform their respective baselines at the same embedding dimensionality, with the reverse-distilled 15 billion parameter model achieving the strongest performance. Our framework is generalizable to any model family where scaling challenges persist. Code and trained models are available at https://github.com/rohitsinghlab/plm_reverse_distillation.

Darius Catrina
Christian Bepler
Samuel Sledzieski
Rohit Singh


Inference-Time Toxicity Mitigation in Protein Language Models

Abstract: Protein language models (PLMs) are becoming practical tools for de novo protein design, yet their dual-use potential raises safety concerns. We show that domain adaptation to specific taxonomic groups can elicit toxic protein generation, even when toxicity is not the training objective. To address this, we adapt Logit Diff Amplification (LDA) as an inference-time control mechanism for PLMs. LDA modifies token probabilities by amplifying the logit difference between a baseline model and a toxicity-finetuned model, requiring no retraining. Across four taxonomic groups, LDA consistently reduces predicted toxicity rate (measured via ToxDL2) below the taxon-finetuned baseline while preserving biological plausibility. We evaluate quality using Fréchet ESM Distance and predicted foldability (pLDDT), finding that LDA maintains distributional similarity to natural proteins and structural viability (unlike activation-based steering methods that tend to degrade sequence properties). Our results demonstrate that LDA provides a practical safety knob for protein generators that mitigates elicited toxicity while retaining generative quality.

Manuel Fernández Burda
Santiago Aranguri
Iván Arcuschin Moreno
Enzo Ferrante


Building a Strong Instruction Language Model for a Less-Resourced Language

Abstract: Large language models (LLMs) have become an essential tool for natural language processing and artificial intelligence in general. Current open-source models are primarily trained on English texts, resulting in poorer performance on less-resourced languages and cultures. We present a set of methodological approaches necessary for the successful adaptation of an LLM to a less-resourced language, and demonstrate them using the Slovene language. We present GaMS3-12B, a generative model for Slovene with 12 billion parameters, and demonstrate that it is the best-performing open-source model for Slovene within its parameter range. We adapted the model to the Slovene language using three-stage continual pre-training of the Gemma 3 model, followed by two-stage supervised fine-tuning (SFT). We trained the model on a combination of 140B Slovene, English, Bosnian, Serbian, and Croatian pretraining tokens, and over 200 thousand English and Slovene SFT examples. We evaluate GaMS3-12B on the Slovenian-LLM-Eval datasets, English-to-Slovene translation, and the Slovene LLM arena. We show that the described model outperforms 12B Gemma 3 across all three scenarios and performs comparably to much larger commercial GPT-4o in the Slovene LLM arena, achieving a win rate of over 60 %.

Domen Vreš
Tjaša Arčon
Timotej Petrič
Dario Vajda
Marko Robnik-Šikonja
Iztok Lebar Bajec


CoPeP: Benchmarking Continual Pretraining for Protein Language Models

Abstract: Protein language models (pLMs) have recently gained significant attention for their ability to uncover relationships between sequence, structure, and function from evolutionary statistics, thereby accelerating therapeutic drug discovery. These models learn from large protein databases that are continuously updated by the biology community and whose dynamic nature motivates the application of continual learning, not only to keep up with the ever-growing data, but also as an opportunity to take advantage of the temporal meta-information that is created during this process. As a result, we introduce the Continual Pretraining of Protein Language Models (CoPeP) benchmark, a novel benchmark for evaluating continual learning approaches on pLMs. Specifically, we curate a sequence of protein datasets derived from the UniProt Knowledgebase spanning a decade and define metrics to assess pLM performance across 31 protein understanding tasks. We evaluate several methods from the continual learning literature, including replay, unlearning, and plasticity-based methods, some of which have never been applied to models and data of this scale. Our findings reveal that incorporating temporal meta-information improves perplexity by up to 7% even when compared to training on data from all tasks jointly. Moreover, even at scale, several continual learning methods outperform naive continual pretraining. The CoPeP benchmark offers an exciting opportunity to study these methods at scale in an impactful real-world application.

Darshan Patil
Pranshu Malviya
Mathieu Reymond
Quentin Fournier
Sarath Chandar


Protein Language Models Diverge from Natural Language: Comparative Analysis and Improved Inference

Abstract: Modern Protein Language Models (PLMs) apply transformer-based model architectures from natural language processing to biological sequences, predicting a variety of protein functions and properties. However, protein language has key differences from natural language, such as a rich functional space despite a vocabulary of only 20 amino acids. These differences motivate research into how transformer-based architectures operate differently in the protein domain and how we can better leverage PLMs to solve protein-related tasks. In this work, we begin by directly comparing how the distribution of information stored across layers of attention heads differs between the protein and natural language domain. Furthermore, we adapt a simple early-exit technique-originally used in the natural language domain to improve efficiency at the cost of performance-to achieve both increased accuracy and substantial efficiency gains in protein non-structural property prediction by allowing the model to automatically select protein representations from the intermediate layers of the PLMs for the specific task and protein at hand. We achieve performance gains ranging from 0.4 to 7.01 percentage points while simultaneously improving efficiency by over 10 percent across models and non-structural prediction tasks. Our work opens up an area of research directly comparing how language models change behavior when moved into the protein domain and advances language modeling in biological domains.

Anna Hart
Chi Han
Jeonghwan Kim
Huimin Zhao
Heng Ji


BeamVLM for Low-altitude Economy: Generative Beam Prediction via Vision-language Models

Abstract: For low-altitude economy (LAE), fast and accurate beam prediction between high-mobility unmanned aerial vehicles (UAVs) and ground base stations is of paramount importance, which ensures seamless coverage and reliable communications. However, existing deep learning-based beam prediction methods lack high-level semantic understanding of dynamic environments, resulting in poor generalization. On the other hand, the emerging large language model (LLM) based approaches show promise in enhancing generalization, but they typically lack rich environmental perception, thereby failing to capture fine-grained spatial semantics essential for precise beam alignment. To tackle these limitations, we propose in this correspondence a novel end-to-end generative framework for beam prediction, called BeamVLM, which treats beam prediction as a vision question answering task capitalizing on powerful existing vision-language models (VLMs). By projecting raw visual patches directly into the language domain and judiciously designing an instructional prompt, the proposed BeamVLM enables the VLM to jointly reason over UAV trajectories and environmental context. Last, experimental results on real-world datasets demonstrate that the proposed BeamVLM outperforms state-of-the-art methods in prediction accuracy and also exhibits superior generalization for other scenarios such as vehicle-to-infrastructure (V2I) beam prediction.

Chenran Kou
Changsheng You
Mingjiang Wu
Dingzhu Wen
Zezhong Zhang
Chengwen Xing


STProtein: predicting spatial protein expression from multi-omics data

Abstract: The integration of spatial multi-omics data from single tissues is crucial for advancing biological research. However, a significant data imbalance impedes progress: while spatial transcriptomics data is relatively abundant, spatial proteomics data remains scarce due to technical limitations and high costs. To overcome this challenge we propose STProtein, a novel framework leveraging graph neural networks with multi-task learning strategy. STProtein is designed to accurately predict unknown spatial protein expression using more accessible spatial multi-omics data, such as spatial transcriptomics. We believe that STProtein can effectively addresses the scarcity of spatial proteomics, accelerating the integration of spatial multi-omics and potentially catalyzing transformative breakthroughs in life sciences. This tool enables scientists to accelerate discovery by identifying complex and previously hidden spatial patterns of proteins within tissues, uncovering novel relationships between different marker genes, and exploring the biological "Dark Matter".

Zhaorui Jiang
Yingfang Yuan
Lei Hu
Wei Pang


Controlling Repetition in Protein Language Models

Abstract: Protein language models (PLMs) have enabled advances in structure prediction and de novo protein design, yet they frequently collapse into pathological repetition during generation. Unlike in text, where repetition merely reduces readability, in proteins it undermines structural confidence and functional viability. To unify this problem, we present the first systematic study of repetition in PLMs. We first propose quantitative metrics to characterize motif-level and homopolymer repetition and then demonstrate their negative impact on folding reliability. To address this challenge, we propose UCCS (Utility-Controlled Contrastive Steering), which steers protein generation with a constrained dataset. Instead of naively contrasting high- vs. low-repetition sequences, we construct contrastive sets that maximize differences in repetition while tightly controlling for structural utility. This disentanglement yields steering vectors that specifically target repetition without degrading foldability. Injected at inference, these vectors consistently reduce repetition without retraining or heuristic decoding. Experiments with ESM-3 and ProtGPT2 in CATH, UniRef50, and SCOP show that our method outperforms decoding penalties and other baselines, substantially lowering repetition while preserving AlphaFold confidence scores. Our results establish repetition control as a central challenge for PLMs and highlight dataset-guided steering as a principled approach for reliable protein generation.

Jiahao Zhang
Zeqing Zhang
Di Wang
Lijie Hu


CalPro: Prior-Aware Evidential--Conformal Prediction with Structure-Aware Guarantees for Protein Structures

Abstract: Deep protein structure predictors such as AlphaFold provide confidence estimates (e.g., pLDDT) that are often miscalibrated and degrade under distribution shifts across experimental modalities, temporal changes, and intrinsically disordered regions. We introduce CalPro, a prior-aware evidential-conformal framework for shift-robust uncertainty quantification. CalPro combines (i) a geometric evidential head that outputs Normal-Inverse-Gamma predictive distributions via a graph-based architecture; (ii) a differentiable conformal layer that enables end-to-end training with finite-sample coverage guarantees; and (iii) domain priors (disorder, flexibility) encoded as soft constraints. We derive structure-aware coverage guarantees under distribution shift using PAC-Bayesian bounds over ambiguity sets, and show that CalPro maintains near-nominal coverage while producing tighter intervals than standard conformal methods in regions where priors are informative. Empirically, CalPro exhibits at most 5% coverage degradation across modalities (vs. 15-25% for baselines), reduces calibration error by 30-50%, and improves downstream ligand-docking success by 25%. Beyond proteins, CalPro applies to structured regression tasks in which priors encode local reliability, validated on non-biological benchmarks.

Ibne Farabi Shihab
Sanjeda Akter
Anuj Sharma


Knowledge Distillation of a Protein Language Model Yields a Foundational Implicit Solvent Model

Abstract: Implicit solvent models (ISMs) promise to deliver the accuracy of explicit solvent simulations at a fraction of the computational cost. However, despite decades of development, their accuracy has remained insufficient for many critical applications, particularly for simulating protein folding and the behavior of intrinsically disordered proteins. Developing a transferable, data-driven ISM that overcomes the limitations of traditional analytical formulas remains a central challenge in computational chemistry. Here we address this challenge by introducing a novel strategy that distills the evolutionary information learned by a protein language model, ESM3, into a computationally efficient graph neural network (GNN). We show that this GNN potential, trained on effective energies from ESM3, is robust enough to drive stable, long-timescale molecular dynamics simulations. When combined with a standard electrostatics term, our hybrid model accurately reproduces protein folding free-energy landscapes and predicts the structural ensembles of intrinsically disordered proteins. This approach yields a single, unified model that is transferable across both folded and disordered protein states, resolving a long-standing limitation of conventional ISMs. By successfully distilling evolutionary knowledge into a physical potential, our work delivers a foundational implicit solvent model poised to accelerate the development of predictive, large-scale simulation tools.


Quantum Simulation of Protein Fragment Electronic Structure Using Moment-based Adaptive Variational Quantum Algorithms

Abstract: Background: Understanding electronic interactions in protein active sites is fundamental to drug discovery and enzyme engineering, but remains computationally challenging due to exponential scaling of quantum mechanical calculations. Results: We present a quantum-classical hybrid framework for simulating protein fragment electronic structure using variational quantum algorithms. We construct fermionic Hamiltonians from experimentally determined protein structures, map them to qubits via Jordan-Wigner transformation, and optimize ground state energies using the Variational Quantum Eigensolver implemented in pure Python. For a 4-orbital serine protease fragment, we achieve chemical accuracy (< 1.6 mHartree) with 95.3% correlation energy recovery. Systematic analysis reveals three-phase convergence behaviour with exponential decay (α = 0.95), power law optimization (γ = 1.21), and asymptotic approach. Application to SARS-CoV-2 protease inhibition demonstrates predictive accuracy (MAE=0.25 kcal/mol), while cytochrome P450 metabolism predictions achieve 85% site accuracy. Conclusions: This work establishes a pathway for quantum-enhanced biomolecular simulations on near-term quantum hardware, bridging quantum algorithm development with practical biological applications.


Physio-DPO: Aligning Large Language Models with the Protein Energy Landscape to Eliminate Structural Hallucinations

Abstract: Large Protein Language Models have shown strong potential for generative protein design, yet they frequently produce structural hallucinations, generating sequences with high linguistic likelihood that fold into thermodynamically unstable conformations. Existing alignment approaches such as Direct Preference Optimization are limited in this setting, as they model preferences as binary labels and ignore the continuous structure of the physical energy landscape. We propose Physio-DPO, a physics informed alignment framework that grounds protein language models in thermodynamic stability. Physio-DPO introduces a magnitude aware objective that scales optimization updates according to the energy gap between native structures and physics perturbed hard negatives. Experiments show that Physio-DPO consistently outperforms strong baselines including SFT, PPO, and standard DPO, reducing self consistency RMSD to 1.28 Å and increasing foldability to 92.8%. Qualitative analysis further demonstrates that Physio-DPO effectively mitigates structural hallucinations by recovering biophysical interactions such as hydrophobic core packing and hydrogen bond networks.


HD-Prot: A Protein Language Model for Joint Sequence-Structure Modeling with Continuous Structure Tokens

Abstract: Proteins inherently possess a consistent sequence-structure duality. The abundance of protein sequence data, which can be readily represented as discrete tokens, has driven fruitful developments in protein language models (pLMs). A key remaining challenge, however, is how to effectively integrate continuous structural knowledge into pLMs. Current methods often discretize protein structures to accommodate the language modeling framework, which inevitably results in the loss of fine-grained information and limits the performance potential of multimodal pLMs. In this paper, we argue that such concerns can be circumvented: a sequence-based pLM can be extended to incorporate the structure modality through continuous tokens, i.e., high-fidelity protein structure latents that avoid vector quantization. Specifically, we propose a hybrid diffusion protein language model, HD-Prot, which embeds a continuous-valued diffusion head atop a discrete pLM, enabling seamless operation with both discrete and continuous tokens for joint sequence-structure modeling. It captures inter-token dependencies across modalities through a unified absorbing diffusion process, and estimates per-token distributions via categorical prediction for sequences and continuous diffusion for structures. Extensive results demonstrate that HD-Prot achieves competitive performance in unconditional sequence-structure co-generation, motif-scaffolding, protein structure prediction, and inverse folding tasks. Furthermore, our method can perform on par with state-of-the-art multimodal pLMs, despite being developed under limited computational resources (i.e., less than one-tenth the budget for modality extension fine-tuning). It highlights the viability of simultaneously estimating categorical and continuous distributions within a unified language model architecture, offering a promising alternative direction for multimodal pLMs.

Yi Zhou
Haohao Qu
Yunqing Liu
Shanru Lin
Le Song
Wenqi Fan


Large language models have learned to use language

Abstract: Acknowledging that large language models have learned to use language can open doors to breakthrough language science. Achieving these breakthroughs may require abandoning some long-held ideas about how language knowledge is evaluated and reckoning with the difficult fact that we have entered a post-Turing test era.


Self Distillation Fine-Tuning of Protein Language Models Improves Versatility in Protein Design

Abstract: Supervised fine-tuning (SFT) is a standard approach for adapting large language models to specialized domains, yet its application to protein sequence modeling and protein language models (PLMs) remains ad hoc. This is in part because high-quality annotated data are far more difficult to obtain for proteins than for natural language. We present a simple and general recipe for fast SFT of PLMs, designed to improve the fidelity, reliability, and novelty of generated protein sequences. Unlike existing approaches that require costly precompiled experimental datasets for SFT, our method leverages the PLM itself, integrating a lightweight curation pipeline with domain-specific filters to construct high-quality training data. These filters can independently refine a PLM's output and identify candidates for in vitro evaluation; when combined with SFT, they enable PLMs to generate more stable and functional enzymes, while expanding exploration into protein sequence space beyond natural variants. Although our approach is agnostic to both the choice of protein language model (PLM) and the protein system, we demonstrate its effectiveness with a genome-scale PLM (GenSLM) applied to the tryptophan synthase enzyme family. The supervised fine-tuned model generates sequences that are not only more novel but also display improved characteristics across both targeted design constraints and emergent protein property measures.

Amin Tavakoli
Raswanth Murugan
Ozan Gokdemir
Arvind Ramanathan
Frances Arnold
Anima Anandkumar


Soft Inductive Bias Approach via Explicit Reasoning Perspectives in Inappropriate Utterance Detection Using Large Language Models

Abstract: Recent incidents in certain online games and communities, where anonymity is guaranteed, show that unchecked inappropriate remarks frequently escalate into verbal abuse and even criminal behavior, raising significant social concerns. Consequently, there is a growing need for research on techniques that can detect inappropriate utterances within conversational texts to help build a safer communication environment. Although large-scale language models trained on Korean corpora and chain-of-thought reasoning have recently gained attention, research applying these approaches to inappropriate utterance detection remains limited. In this study, we propose a soft inductive bias approach that explicitly defines reasoning perspectives to guide the inference process, thereby promoting rational decision-making and preventing errors that may arise during reasoning. We fine-tune a Korean large language model using the proposed method and conduct both quantitative performance comparisons and qualitative evaluations across different training strategies. Experimental results show that the Kanana-1.5 model achieves an average accuracy of 87.0046, improving by approximately 3.89 percent over standard supervised learning. These findings indicate that the proposed method goes beyond simple knowledge imitation by large language models and enables more precise and consistent judgments through constrained reasoning perspectives, demonstrating its effectiveness for inappropriate utterance detection.

Ju-Young Kim
Ji-Hong Park
Se-Yeon Lee
Sujin Park
Gun-Woo Kim


Protein Secondary Structure Prediction Using Transformers

Abstract: Predicting protein secondary structures such as alpha helices, beta sheets, and coils from amino acid sequences is essential for understanding protein function. This work presents a transformer-based model that applies attention mechanisms to protein sequence data to predict structural motifs. A sliding-window data augmentation technique is used on the CB513 dataset to expand the training samples. The transformer shows strong ability to generalize across variable-length sequences while effectively capturing both local and long-range residue interactions.


Classifying German Language Proficiency Levels Using Large Language Models

Abstract: Assessing language proficiency is essential for education, as it enables instruction tailored to learners needs. This paper investigates the use of Large Language Models (LLMs) for automatically classifying German texts according to the Common European Framework of Reference for Languages (CEFR) into different proficiency levels. To support robust training and evaluation, we construct a diverse dataset by combining multiple existing CEFR-annotated corpora with synthetic data. We then evaluate prompt-engineering strategies, fine-tuning of a LLaMA-3-8B-Instruct model and a probing-based approach that utilizes the internal neural state of the LLM for classification. Our results show a consistent performance improvement over prior methods, highlighting the potential of LLMs for reliable and scalable CEFR classification.

Elias-Leander Ahlers
Witold Brunsmann
Malte Schilling


Small Language Models Reshape Higher Education: Courses, Textbooks, and Teaching

Abstract: While large language models (LLMs) have introduced novel paradigms in science and education, their adoption in higher education is constrained by inherent limitations. These include a tendency to produce inaccuracies and high computational requirements, which compromise the strict demands for accurate and reliable knowledge essential in higher education. Small language models (MiniLMs), by contrast, offer distinct advantages in professional education due to their lightweight nature and precise retrieval capabilities. This research takes "Atmospheric Physics" as an example. We established a specialized corpus and image repository by gathering over 550,000 full-text PDFs from over 130 international well-respected journals in Earth and environmental science. From this collection, we extracted over 100 million high-quality sentence-level corpus and more than 3 million high-resolution academic images. Using MiniLMs, these resources were organized into a high-dimensional vector library for precise retrieval and efficient utilization of extensive educational content. Consequently, we systematically redesigned the courses, textbooks, and teaching strategies for "Atmospheric Physics" based on MiniLMs. The course is designed as a "interdisciplinary-frontier" system, breaking down traditional boundaries between atmospheric science, space science, hydrology, and remote sensing. Teaching materials are transformed from static, lagging text formats into a dynamic digital resource library powered by MiniLM. For teaching methods, we have designed a question-based learning pathway. This paradigm promotes a shift from passive knowledge transfer to active cognitive development. Consequently, this MiniLM-driven "Atmospheric Physics" course demonstrates a specific avenue for "AI for education".


Layer Probing Improves Kinase Functional Prediction with Protein Language Models

Abstract: Protein language models (PLMs) have transformed sequence-based protein analysis, yet most applications rely only on final-layer embeddings, which may overlook biologically meaningful information encoded in earlier layers. We systematically evaluate all 33 layers of ESM-2 for kinase functional prediction using both unsupervised clustering and supervised classification. We show that mid-to-late transformer layers (layers 20-33) outperform the final layer by 32 percent in unsupervised Adjusted Rand Index and improve homology-aware supervised accuracy to 75.7 percent. Domain-level extraction, calibrated probability estimates, and a reproducible benchmarking pipeline further strengthen reliability. Our results demonstrate that transformer depth contains functionally distinct biological signals and that principled layer selection significantly improves kinase function prediction.


Language-conditioned world model improves policy generalization by reading environmental descriptions

Abstract: To interact effectively with humans in the real world, it is important for agents to understand language that describes the dynamics of the environment--that is, how the environment behaves--rather than just task instructions specifying "what to do". Understanding this dynamics-descriptive language is important for human-agent interaction and agent behavior. Recent work address this problem using a model-based approach: language is incorporated into a world model, which is then used to learn a behavior policy. However, these existing methods either do not demonstrate policy generalization to unseen games or rely on limiting assumptions. For instance, assuming that the latency induced by inference-time planning is tolerable for the target task or expert demonstrations are available. Expanding on this line of research, we focus on improving policy generalization from a language-conditioned world model while dropping these assumptions. We propose a model-based reinforcement learning approach, where a language-conditioned world model is trained through interaction with the environment, and a policy is learned from this model--without planning or expert demonstrations. Our method proposes Language-aware Encoder for Dreamer World Model (LED-WM) built on top of DreamerV3. LED-WM features an observation encoder that uses an attention mechanism to explicitly ground language descriptions to entities in the observation. We show that policies trained with LED-WM generalize more effectively to unseen games described by novel dynamics and language compared to other baselines in several settings in two environments: MESSENGER and MESSENGER-WM.To highlight how the policy can leverage the trained world model before real-world deployment, we demonstrate the policy can be improved through fine-tuning on synthetic test trajectories generated by the world model.


Swarms of Large Language Model Agents for Protein Sequence Design with Experimental Validation

Abstract: Designing proteins de novo with tailored structural, physicochemical, and functional properties remains a grand challenge in biotechnology, medicine, and materials science, due to the vastness of sequence space and the complex coupling between sequence, structure, and function. Current state-of-the-art generative methods, such as protein language models (PLMs) and diffusion-based architectures, often require extensive fine-tuning, task-specific data, or model reconfiguration to support objective-directed design, thereby limiting their flexibility and scalability. To overcome these limitations, we present a decentralized, agent-based framework inspired by swarm intelligence for de novo protein design. In this approach, multiple large language model (LLM) agents operate in parallel, each assigned to a specific residue position. These agents iteratively propose context-aware mutations by integrating design objectives, local neighborhood interactions, and memory and feedback from previous iterations. This position-wise, decentralized coordination enables emergent design of diverse, well-defined sequences without reliance on motif scaffolds or multiple sequence alignments, validated with experiments on proteins with alpha helix and coil structures. Through analyses of residue conservation, structure-based metrics, and sequence convergence and embeddings, we demonstrate that the framework exhibits emergent behaviors and effective navigation of the protein fitness landscape. Our method achieves efficient, objective-directed designs within a few GPU-hours and operates entirely without fine-tuning or specialized training, offering a generalizable and adaptable solution for protein design. Beyond proteins, the approach lays the groundwork for collective LLM-driven design across biomolecular systems and other scientific discovery tasks.

Fiona Y. Wang
Di Sheng Lee
David L. Kaplan
Markus J. Buehler


DeepPNI: Language- and graph-based model for mutation-driven protein-nucleic acid energetics

Abstract: The interaction between proteins and nucleic acids is crucial for processes that sustain cellular function, including DNA maintenance and the regulation of gene expression and translation. Amino acid mutations in protein-nucleic acid complexes often lead to vital diseases. Experimental techniques have their own specific limitations in predicting mutational effects in protein-nucleic acid complexes. In this study, we compiled a large dataset of 1951 mutations including both protein-DNA and protein-RNA complexes and integrated structural and sequential features to build a deep learning-based regression model named DeepPNI. This model estimates mutation-induced binding free energy changes in protein-nucleic acid complexes. The structural features are encoded via edge-aware RGCN and the sequential features are extracted using protein language model ESM-2. We have achieved a high average Pearson correlation coefficient (PCC) of 0.76 in the large dataset via five-fold cross-validation. Consistent performance across individual dataset of protein-DNA, protein-RNA complexes, and different experimental temperature split dataset make the model generalizable. Our model showed good performance in complex-based five-fold cross-validation, which proved its robustness. In addition, DeepPNI outperformed in external dataset validation, and comparison with existing tools

Somnath Mondal
Tinkal Mondal
Soumajit Pramanik
Rukmankesh Mehra


Protein Secondary Structure Prediction Using 3D Graphs and Relation-Aware Message Passing Transformers

Abstract: In this study, we tackle the challenging task of predicting secondary structures from protein primary sequences, a pivotal initial stride towards predicting tertiary structures, while yielding crucial insights into protein activity, relationships, and functions. Existing methods often utilize extensive sets of unlabeled amino acid sequences. However, these approaches neither explicitly capture nor harness the accessible protein 3D structural data, which is recognized as a decisive factor in dictating protein functions. To address this, we utilize protein residue graphs and introduce various forms of sequential or structural connections to capture enhanced spatial information. We adeptly combine Graph Neural Networks (GNNs) and Language Models (LMs), specifically utilizing a pre-trained transformer-based protein language model to encode amino acid sequences and employing message-passing mechanisms like GCN and R-GCN to capture geometric characteristics of protein structures. Employing convolution within a specific node's nearby region, including relations, we stack multiple convolutional layers to efficiently learn combined insights from the protein's spatial graph, revealing intricate interconnections and dependencies in its structural arrangement. To assess our model's performance, we employed the training dataset provided by NetSurfP-2.0, which outlines secondary structure in 3-and 8-states. Extensive experiments show that our proposed model, SSRGNet surpasses the baseline on f1-scores.

Disha Varshney
Samarth Garg
Sarthak Tyagi
Deeksha Varshney
Nayan Deep
Asif Ekbal


Studies with impossible languages falsify LMs as models of human language

Abstract: According to Futrell and Mahowald [arXiv:2501.17047], both infants and language models (LMs) find attested languages easier to learn than impossible languages that have unnatural structures. We review the literature and show that LMs often learn attested and many impossible languages equally well. Difficult to learn impossible languages are simply more complex (or random). LMs are missing human inductive biases that support language acquisition.


Boosting In-Silicon Directed Evolution with Fine-Tuned Protein Language Model and Tree Search

Abstract: Protein evolution through amino acid mutations is a cornerstone of life sciences. Recent advances in protein language models have shown rich evolutionary patterns, offering unprecedented potential for in-silicon directed evolution. However, existing directed evolution methods largely rely on heuristic evolution strategies and have yet to efficiently integrate the transformative protein language models with advanced optimization techniques, such as reinforcement learning, to adaptively learn superior evolution policies. To bridge this gap, we propose AlphaDE, a novel framework that evolves protein sequences by harnessing the innovative paradigms of large language models, such as fine-tuning and test-time inference. First, AlphaDE fine-tunes pretrained protein language models using masked language modeling on homologous protein sequences to activate the evolutionary plausibility of the interested protein family. Second, AlphaDE introduces test-time inference based on Monte Carlo tree search, which effectively evolves proteins with evolutionary guidance from the fine-tuned protein language model. Extensive benchmark experiments show that AlphaDE remarkably outperforms previous state-of-the-art methods even with few-shot fine-tuning. A case study further demonstrates that AlphaDE supports condensing the protein sequence space of avGFP through computational evolution.

Yaodong Yang
Yang Wang
Jinpeng Li
Pei Guo
Da Han
Guangyong Chen
Pheng-Ann Heng


From Static Structures to Ensembles: Studying and Harnessing Protein Structure Tokenization

Abstract: 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.


Joint Design of Protein Surface and Structure Using a Diffusion Bridge Model

Abstract: Protein-protein interactions (PPIs) are governed by surface complementarity and hydrophobic interactions at protein interfaces. However, designing diverse and physically realistic protein structure and surfaces that precisely complement target receptors remains a significant challenge in computational protein design. In this work, we introduce PepBridge, a novel framework for the joint design of protein surface and structure that seamlessly integrates receptor surface geometry and biochemical properties. Starting with a receptor surface represented as a 3D point cloud, PepBridge generates complete protein structures through a multi-step process. First, it employs denoising diffusion bridge models (DDBMs) to map receptor surfaces to ligand surfaces. Next, a multi-model diffusion model predicts the corresponding structure, while Shape-Frame Matching Networks ensure alignment between surface geometry and backbone architecture. This integrated approach facilitates surface complementarity, conformational stability, and chemical feasibility. Extensive validation across diverse protein design scenarios demonstrates PepBridge's efficacy in generating structurally viable proteins, representing a significant advancement in the joint design of top-down protein structure.

Guanlue Li
Xufeng Zhao
Fang Wu
Sören Laue


Quantifying the Role of OpenFold Components in Protein Structure Prediction

Abstract: Models such as AlphaFold2 and OpenFold have transformed protein structure prediction, yet their inner workings remain poorly understood. We present a methodology to systematically evaluate the contribution of individual OpenFold components to structure prediction accuracy. We identify several components that are critical for most proteins, while others vary in importance across proteins. We further show that the contribution of several components is correlated with protein length. These findings provide insight into how OpenFold achieves accurate predictions and highlight directions for interpreting protein prediction networks more broadly.


GeoPep: A geometry-aware masked language model for protein-peptide binding site prediction

Abstract: Multimodal approaches that integrate protein structure and sequence have achieved remarkable success in protein-protein interface prediction. However, extending these methods to protein-peptide interactions remains challenging due to the inherent conformational flexibility of peptides and the limited availability of structural data that hinder direct training of structure-aware models. To address these limitations, we introduce GeoPep, a novel framework for peptide binding site prediction that leverages transfer learning from ESM3, a multimodal protein foundation model. GeoPep fine-tunes ESM3's rich pre-learned representations from protein-protein binding to address the limited availability of protein-peptide binding data. The fine-tuned model is further integrated with a parameter-efficient neural network architecture capable of learning complex patterns from sparse data. Furthermore, the model is trained using distance-based loss functions that exploit 3D structural information to enhance binding site prediction. Comprehensive evaluations demonstrate that GeoPep significantly outperforms existing methods in protein-peptide binding site prediction by effectively capturing sparse and heterogeneous binding patterns.

Dian Chen
Yunkai Chen
Tong Lin
Sijie Chen
Xiaolin Cheng


Precision Design of Cyclic Peptides using AlphaFold

Abstract: This independent research investigates methods to improve the precision of cyclic peptide generation targeting the HIV gp120 trimer using AlphaFold. The study explores proximity-based hotspot mapping at the CD4 binding site, centroid distance penalization, generative loss tuning, and custom loss function development. These enhancements produced cyclic peptides that closely resemble the binding conformation of the CD4 attachment inhibitor BMS-818251. The proposed methodology demonstrates improved structural control and precision in cyclic peptide generation, advancing the applicability of AlphaFold in structure-based drug discovery.


Protein as a Second Language for LLMs

Abstract: Deciphering the function of unseen protein sequences is a fundamental challenge with broad scientific impact, yet most existing methods depend on task-specific adapters or large-scale supervised fine-tuning. We introduce the "Protein-as-Second-Language" framework, which reformulates amino-acid sequences as sentences in a novel symbolic language that large language models can interpret through contextual exemplars. Our approach adaptively constructs sequence-question-answer triples that reveal functional cues in a zero-shot setting, without any further training. To support this process, we curate a bilingual corpus of 79,926 protein-QA instances spanning attribute prediction, descriptive understanding, and extended reasoning. Empirically, our method delivers consistent gains across diverse open-source LLMs and GPT-4, achieving up to 17.2% ROUGE-L improvement (average +7%) and even surpassing fine-tuned protein-specific language models. These results highlight that generic LLMs, when guided with protein-as-language cues, can outperform domain-specialized models, offering a scalable pathway for protein understanding in foundation models.

Xinhui Chen
Zuchao Li
Mengqi Gao
Yufeng Zhang
Chak Tou Leong
Haoyang Li
Jiaqi Chen


A Hybrid Quantum-AI Framework for Protein Structure Prediction on NISQ Devices

Abstract: Variational quantum algorithms provide a direct, physics-based approach to protein structure prediction, but their accuracy is limited by the coarse resolution of the energy landscapes generated on current noisy devices. We propose a hybrid framework that combines quantum computation with deep learning, formulating structure prediction as a problem of energy fusion. Candidate conformations are obtained through the Variational Quantum Eigensolver (VQE) executed on IBM's 127-qubit superconducting processor, which defines a global yet low-resolution quantum energy surface. To refine these basins, secondary structure probabilities and dihedral angle distributions predicted by the NSP3 neural network are incorporated as statistical potentials. These additional terms sharpen the valleys of the quantum landscape, resulting in a fused energy function that enhances effective resolution and better distinguishes native-like structures. Evaluation on 375 conformations from 75 protein fragments shows consistent improvements over AlphaFold3, ColabFold, and quantum-only predictions, achieving a mean RMSD of 4.9 Å with statistical significance (p < 0.001). The findings demonstrate that energy fusion offers a systematic method for combining data-driven models with quantum algorithms, improving the practical applicability of near-term quantum computing to molecular and structural biology.

Yuqi Zhang
Yuxin Yang
Feixiong Chen
Cheng-Chang Lu
Nima Saeidi
Samuel L. Volchenboum
Junhan Zhao
Siwei Chen
Weiwen Jiang
Qiang Guan


Attending on Multilevel Structure of Proteins enables Accurate Prediction of Cold-Start Drug-Target Interactions

Abstract: Cold-start drug-target interaction (DTI) prediction focuses on interaction between novel drugs and proteins. Previous methods typically learn transferable interaction patterns between structures of drug and proteins to tackle it. However, insight from proteomics suggest that protein have multi-level structures and they all influence the DTI. Existing works usually represent protein with only primary structures, limiting their ability to capture interactions involving higher-level structures. Inspired by this insight, we propose ColdDTI, a framework attending on protein multi-level structure for cold-start DTI prediction. We employ hierarchical attention mechanism to mine interaction between multi-level protein structures (from primary to quaternary) and drug structures at both local and global granularities. Then, we leverage mined interactions to fuse structure representations of different levels for final prediction. Our design captures biologically transferable priors, avoiding the risk of overfitting caused by excessive reliance on representation learning. Experiments on benchmark datasets demonstrate that ColdDTI consistently outperforms previous methods in cold-start settings.

Ziying Zhang
Yaqing Wang
Yuxuan Sun
Min Ye
Quanming Yao


Model Merging to Maintain Language-Only Performance in Developmentally Plausible Multimodal Models

Abstract: State-of-the-art vision-and-language models consist of many parameters and learn from enormous datasets, surpassing the amounts of linguistic data that children are exposed to as they acquire a language. This paper presents our approach to the multimodal track of the BabyLM challenge addressing this discrepancy. We develop language-only and multimodal models in low-resource settings using developmentally plausible datasets, with our multimodal models outperforming previous BabyLM baselines. One finding in the multimodal language model literature is that these models tend to underperform in \textit{language-only} tasks. Therefore, we focus on maintaining language-only abilities in multimodal models. To this end, we experiment with \textit{model merging}, where we fuse the parameters of multimodal models with those of language-only models using weighted linear interpolation. Our results corroborate the findings that multimodal models underperform in language-only benchmarks that focus on grammar, and model merging with text-only models can help alleviate this problem to some extent, while maintaining multimodal performance.


Type-Less yet Type-Aware Inductive Link Prediction with Pretrained Language Models

Abstract: Inductive link prediction is emerging as a key paradigm for real-world knowledge graphs (KGs), where new entities frequently appear and models must generalize to them without retraining. Predicting links in a KG faces the challenge of guessing previously unseen entities by leveraging generalizable node features such as subgraph structure, type annotations, and ontological constraints. However, explicit type information is often lacking or incomplete. Even when available, type information in most KGs is often coarse-grained, sparse, and prone to errors due to human annotation. In this work, we explore the potential of pre-trained language models (PLMs) to enrich node representations with implicit type signals. We introduce TyleR, a Type-less yet type-awaRe approach for subgraph-based inductive link prediction that leverages PLMs for semantic enrichment. Experiments on standard benchmarks demonstrate that TyleR outperforms state-of-the-art baselines in scenarios with scarce type annotations and sparse graph connectivity. To ensure reproducibility, we share our code at https://github.com/sisinflab/tyler .

Alessandro De Bellis
Salvatore Bufi
Giovanni Servedio
Vito Walter Anelli
Tommaso Di Noia
Eugenio Di Sciascio

Conference on Empirical Methods in Natural Language Processing


LAMP-PRo: Label-aware Attention for Multi-label Prediction of DNA- and RNA-binding Proteins using Protein Language Models

Abstract: Identifying DNA- (DBPs) and RNA-binding proteins (RBPs) is crucial for the understanding of cell function, molecular interactions as well as regulatory functions. Owing to their high similarity, most of the existing approaches face challenges in differentiating between DBPs and RBPs leading to high cross-prediction errors. Moreover, identifying proteins which bind to both DNA and RNA (DRBPs) is also quite a challenging task. In this regard, we propose a novel framework viz. LAMP-PRo which is based on pre-trained protein language model (PLM), attention mechanisms and multi-label learning to mitigate these issues. First, pre-trained PLM such ESM-2 is used for embedding the protein sequences followed by convolutional neural network (CNN). Subsequently multi-head self-attention mechanism is applied for the contextual information while label-aware attention is used to compute class-specific representations by attending to the sequence in a way that is tailored to each label (DBP, RBP and non-NABP) in a multi-label setup. We have also included a novel cross-label attention mechanism to explicitly capture dependencies between DNA- and RNA-binding proteins, enabling more accurate prediction of DRBP. Finally, a linear layer followed by a sigmoid function are used for the final prediction. Extensive experiments are carried out to compare LAMP-PRo with the existing methods wherein the proposed model shows consistent competent performance. Furthermore, we also provide visualization to showcase model interpretability, highlighting which parts of the sequence are most relevant for a predicted label. The original datasets are available at http://bliulab.net/iDRBP\_MMC and the codes are available at https://github.com/NimishaGhosh/LAMP-PRo.

Nimisha Ghosh
Dheeran Sankaran
Rahul Balakrishnan Adhi
Sharath S
Amrut Anand


Twin Peaks: Dual-Head Architecture for Structure-Free Prediction of Protein-Protein Binding Affinity and Mutation Effects

Abstract: We present a novel dual-head deep learning architecture for protein-protein interaction modeling that enables simultaneous prediction of binding affinity ($ΔG$) and mutation-induced affinity changes ($ΔΔG$) using only protein sequence information. Our approach offers a significant advancement over existing methods by employing specialized prediction heads that operate on a shared representation network, allowing direct and optimized prediction of both values. To ensure robust generalization, we integrated complementary datasets from SKEMPI v2 and PDBbind with a rigorous protein domain-based splitting strategy that prevents information leakage between training and validation sets. Our architecture combines transformer-based encoders with a novel cross-attention mechanism that processes paired protein sequences directly, without requiring any structural information. The network embeds input sequences using ESM3 representations, then employs a learnable sliced window embedding layer to manage variable-length sequences efficiently. A multi-layer transformer encoder with bidirectional self-attention captures intra-protein patterns, while cross-attention layers enable explicit modeling of interactions between protein pairs. This shared representation network feeds into separate $ΔG$ and $ΔΔG$ prediction heads, allowing task-specific optimization while leveraging common features. The model achieves $ΔΔG$ validation of Pearson correlation at 0.485, while maintaining strong $ΔG$ predictions (Pearson: 0.638). While existing approaches require protein structure data and binding interface information, our model eliminates these constraints. This provides a critical advantage for the numerous proteins with unknown structures or those challenging to crystallize, such as viral and intrinsically disordered proteins.


Efficient Quantum Protein Structure Prediction with Problem-Agnostic Ansatzes

Abstract: Accurately predicting protein structures from amino acid sequences remains a fundamental challenge in computational biology, with profound implications for understanding biological functions and enabling structure-based drug discovery. Quantum computing approaches based on coarse-grained lattice models combined with variational algorithms have been proposed as an initial step towards predicting protein structures using quantum computers. In this work, we introduce a more efficient quantum protein structure prediction workflow that bypasses the need for explicit Hamiltonian construction by employing a problem-agnostic ansatz. The ansatz is trained to minimize an energy-based cost function that can be efficiently computed on classical computers, eliminating the need for ancillary qubits and reducing circuit depth compared to previous Hamiltonian-based methods. This enables a more scalable approach for larger proteins and facilitates the inclusion of higher-order interactions, previously hard to achieve in quantum approaches. We validate our method by benchmarking a hardware-efficient ansatz on a large set of proteins with up to 26 amino acids, modeled on the tetrahedral, body-centered cubic, and face-centered cubic lattices, incorporating up to second-nearest-neighbor interactions. We assess the performance on both a noise-free simulator and the ibm_kingston quantum computer using a set of distinct metrics to probe different aspects of the prediction quality. These experiments push the boundaries of quantum methods for protein structure prediction, targeting sequences that are longer than those typically addressed in prior studies. Overall, the results highlight the scalability and versatility of our approach, while also identifying key areas for improvement to inform future algorithm development and hardware advancements.

Hanna Linn
Rui-Hao Li
Alexander Holden
Abdullah Ash Saki
Frank DiFilippo
Tomas Radivoyevitch
Daniel Blankenberg
Laura García-Álvarez
Göran Johansson


From Prediction to Simulation: AlphaFold 3 as a Differentiable Framework for Structural Biology

Abstract: AlphaFold 3 represents a transformative advancement in computational biology, enhancing protein structure prediction through novel multi-scale transformer architectures, biologically informed cross-attention mechanisms, and geometry-aware optimization strategies. These innovations dramatically improve predictive accuracy and generalization across diverse protein families, surpassing previous methods. Crucially, AlphaFold 3 embodies a paradigm shift toward differentiable simulation, bridging traditional static structural modeling with dynamic molecular simulations. By reframing protein folding predictions as a differentiable process, AlphaFold 3 serves as a foundational framework for integrating deep learning with physics-based molecular