Research

• arXiv cs.AIOct 20

  CrystalAR: Autoregressive Modeling for Symmetric Crystal Generation

  Ziqiao Meng, Rongsheng Chen, Zhi Zheng, Nikita Kazeev, Zhenkun Wang +2

  Deep generative modeling has achieved remarkable progress in crystal generation. Given the rich symmetries inherent in crystalline structures, recent work has sought to explicitly incorporate space-group symmetry into generative models, enabling more effective exploration of novel symmetry templates. Yet introducing symmetry templates increases the combinatorial complexity of stoichiometric relationships between atomic species and crystallographic sites, while creating a fundamental tension between flexible exploration of discrete crystallographic templates and faithful realization of these templates as continuous three-dimensional structures. To address these challenges, we propose CrystalAR, a unified autoregressive framework that models Wyckoff symmetry templates and complete crystal structures within a single generative sequence. Specifically, CrystalAR reformulates continuous coordinate generation as a symmetry-conditioned hierarchy of discrete spatial localization decisions, autoregressively refining the positions of all symmetry-inequivalent sites across resolution levels while jointly modeling their spatial configuration within each level. This discrete hierarchical…

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• arXiv cs.LGOct 20

  Ensemble-Aware Structural Encoding (EASE): Conditioning Protein Encoders on Peptide Conformational Ensembles

  Ruoyao Zhang, Hongxuan Li, Jie Peng, Tianlong Chen

  Protein foundation models provide transferable representations for downstream peptide prediction tasks. However, existing representations typically reduce a peptide to a single sequence or structure, which may miss conformational variability relevant to key peptide properties, including antibacterial activity, hemolysis, toxicity, stability, and binding. For example, protease resistance correlates more strongly with conformational dynamics measured by hydrogen exchange than with average helicity. Therefore, we introduce Ensemble-Aware Structural Encoding (EASE), a framework for effectively extracting structural information from conformational ensembles for peptide representation. To extract useful information from noisy conformers, EASE selects central conformers representing a peptide's major structural states and fuses their individual representations with a permutation-invariant operator to produce a peptide-level representation for downstream prediction. We then evaluate our framework on six peptide property-prediction tasks under leakage-controlled splits. Against matched single-structure baselines, EASE improves performance consistently on six tasks with a mean absolute…

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• arXiv cs.LGOct 20

  Learning Inter-Graph Interactions Between Heterogeneous Substructures of Chemical Systems

  Gyoung S. Na

  Complex chemical systems containing heterogeneous substructures are common in real-world applications. Various physical phenomena of the complex chemical systems are derived from the interactions between the heterogeneous substructures. However, existing graph representation learning methods for inter-graph interactions assumed graph-level interactions between homogeneous structures, such as organic molecules and inorganic crystalline materials. We propose a data descriptor of the complex chemical systems and a graph neural network for learning inter-graph interactions between organic and inorganic compounds. We applied the proposed method to predict the physical properties of hybrid solar cell materials containing heterogeneous substructures, which have received significant attention for sustainable energy resources. By learning heterogeneous inter-graph interactions, the proposed method achieved state-of-the-art accuracy in predicting band gaps of 1,682 hybrid solar cell materials.

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• arXiv cond-mat.mtrl-sciOct 20

  Learning the Geometry of Materials Space with Trained Neural Tangent Kernels

  Daniel Kaplan, Gabriel Kotliar, Anirvan M Sengupta

  Neural networks trained to predict materials properties learn representations whose physical content can be difficult to extract. We use the neural tangent kernel (NTK), evaluated at trained parameters, to recover the geometry learned by a network that predicts superconducting transition temperatures from elemental composition alone. Kernel ridge regression with the trained NTK closely reproduces the network's predictive performance and substantially outperforms regression with the initial kernel. Spectral analysis and multidimensional scaling reveal a geometry dominated by a small number of directions. Clustering and local neighborhood analysis organize compounds into recognizable superconducting families and connect materials with related chemical and correlated-electron properties despite substantial differences in $T_c$. These results establish trained tangent kernels as practical probes of learned materials representations, connecting property prediction with the exploration of materials space.

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• arXiv q-bio.QMOct 19

  EMBER: Predicting TCR--pMHC Binding Without a Docked Complex

  Lin Ha, Chen Zhou, Haozheng Luo, Han Liu, Xiaoyu Zhang +1

  We propose EMBER, a structure-based framework for TCR--pMHC binding prediction that eliminates the need for a predicted docked complex, and with it the placement error that dominates such predictions. Traditional structure-based predictors utilize the co-folded complex structure of the receptor and the antigen and interpret binding from its contact surface. Consequently, every downstream feature inherits any deviation the structure-prediction tool introduced. Methodologically, EMBER folds the TCR and pMHC independently, encodes them as SE(3)-invariant residue graphs, and compares their learned representations without constructing a shared coordinate frame. A relative pose is therefore not an input of the model, so placement error cannot propagate into the prediction. Computationally, EMBER preprocesses $O(N{+}M)$ monomer folds where a complex-based predictor needs $O(NM)$ operations. Experimentally, under epitope-disjoint evaluation with six retrained baselines, EMBER is first on every metric under all four folding tools, by 0.9 to 14.4% in micro-AUROC, 18.5 to 25.3% in micro-AUPRC and 10.6 to 24.1% in MCC. Its ranking is also up to 85% more stable across folding tools.

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• arXiv cs.AIOct 19

  Magnolia: A Persistent-Memory Agent Framework for Computational Chemistry

  Tao Jiang, Benjamin Navet, Yousouf Taghzouti, Fabien Gandon, Louis-Félix Nothias +1

  Chemistry has recently entered a high-data regime as molecular databases from high-throughput platforms or computational studies have become available. Increasing automation within the chemical sciences leads to a more digital and precision chemistry. Dedicated scientific agents are becoming central to guiding the chemist through an ever-increasing amount of data and findings, including negative ones. Here, we introduce Magnolia, a persistent-memory artificial intelligence agent framework that integrates computational protocols, from docking to quantum chemistry, lab notebooks and chat logs relying on large language models (LLMs). It relies on a three-tier memory system: session-level observations are automatically captured and distilled into structured learnings, confirmed and elevated to project-tier entries and, when human-validated, promoted to cross-project rules that actively guide subsequent work and provide direct chemical feedback. We illustrate Magnolia on four case studies: quantum-chemical evaluation of aromatic systems (COMPAS database), molecular dynamics of butane and of modified DNA, and a protein-peptide docking campaign. Across these projects, Magnolia tracked…

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• arXiv astro-ph.EPOct 19

  Ammonia-Hydrogen Phase Equilibria in Planetary Envelopes from First-Principles-Based Machine-Learning Molecular Dynamics

  Akash Gupta, Austin Guo, Jie Deng

  Ammonia and hydrogen are major constituents of planets within and beyond the solar system, yet how they interact in planetary envelopes is poorly known. We perform large-scale two-phase coexistence simulations of the ammonia-hydrogen system from 500 to 4000 K and 0.1 to 100 GPa, driven by machine-learning interatomic potentials trained on density functional theory calculations. From these we map the compositions of coexisting hydrogen-rich and ammonia-rich phases, and the critical curve that separates conditions of complete miscibility from those of phase separation. The critical temperature increases with pressure, from 500 K at 0.1 GPa to 2000 K near 30 GPa, and we find no phase separation at 3000 and 4000 K up to 100 GPa. The slope of the critical curve decreases substantially between 0.3 and 30 GPa, and the curve nearly flattens above about 30 GPa and 2000 K, where molecules begin to give way to atomic species. The coexistence curves are asymmetric with an ammonia-rich critical composition. For the expected envelope compositions, the phase boundary lies close to, and intersects, published thermal profiles of Uranus and Neptune, implying ammonia may be raining out in these…

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• arXiv cs.AIOct 19

  ProteinGeoBench: Frontier Structural-Biology Agents Are Fluent at Lookup but Lost in Geometry

  Matt Turk, Brandon L. Neel, Diana M. Lopez, Zachary D. Smith, Grace N. Johnecheck +1

  Frontier agents retrieve structural metadata well and compute geometry from coordinates less reliably. We ask how much of a benchmark score reflects that gap and how much reflects the evaluation configuration around the model. We study ProteinGeoBench, a suite of 131 protein-structure tasks, using 4,249 rollouts from four frontier models and 4,486 further trials across 26 models. Three of the four frontier models fall within 0.031 of one another (0.785 to 0.816) with no difference between them resolved, while the fourth scores 0.707 and all three gaps to it exclude zero. Three of the four do better on metadata lookup than on numeric calculation. The fourth is slightly better on numeric. Numeric tasks are 28 of the 131 but half of the twelve tasks that all four models fail. The ranking also depends on the evaluation budget: with one run per task, 23.9% of bootstrap replicates put a different model first. On a selected 15-task slice, removing network access lowers scores more than blocking eight structural-database domains, but the two contrasts were graded in different passes and cannot be cleanly decomposed. Swapping in each model's own command-line agent changes scores by -0.071…

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• arXiv cs.LGOct 19

  recAMPLIFY: Large-Scale Pretraining of Recursive Protein Language Models

  Saurav Jha, Qianli Liao, Robert Vernon, Sarath Chandar, Quentin Fournier

  Protein language models (pLMs) are powerful tools for protein annotation and mutation-effect prediction, but progress has largely depended on scaling model size and data, making them expensive and prone to memorization. Test-time scaling offers a complementary path, but methods developed for autoregressive LLMs do not transfer directly: masked encoders lack a generation loop, and amino acids do not verbalize in a reasoning language. Instead, we adapt recursive pretraining to masked pLMs, where a weight-tied Transformer core refines residue-aligned hidden states over an adjustable number of cycles. We instantiate this recipe as recAMPLIFY, a pLM with 155M unique parameters trained on the same 2T tokens as AMPLIFY-350M. Despite 56% fewer parameters, it improves CASP contact recovery and three out of four supervised tasks, notably raising fold accuracy by 22.5%. Because optimal depth for recAMPLIFY varies across tasks and assays, we then introduce Gated Mixture Recurrence (GMR), a framework that decodes each protein from a probability-weighted mixture of hidden states visited during recursion. GMR employs a learned residual gate at scalar, low-rank, or per-dimension resolution to…

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• arXiv cs.LGOct 19

  The Effectiveness and Durability of Pretraining Data Filtering in Protein Language Models

  Aaron Maiwald, Roderick McNeill, Jaeyoung Lee, Matthew A. Clarke, Lennart Justen +7

  Pretraining filtering is one of the most common safeguards for open-weight language models. Here we study its effectiveness, durability and scalability using the ESM-2 family of protein language models. We find that filtering viral proteins from the pretraining data meaningfully degrades masked language modelling, mutation effect prediction and long-range contact prediction on viral proteins, while largely preserving performance on non-viral proteins. These effects are concentrated among proteins from human-infecting viruses, and grow as we scale models from 8M to 3B parameters. As models increase in size, we find that stringent filtering becomes more effective. However, fine-tuning on sequences from the removed viral families restores the lost performance. Although the cost to recover performance increases with model scale, even for the largest models it costs about 80 USD of H100 time. This work establishes pretraining filtering as moderately effective at selectively degrading performance on viral proteins, but not durable against fine-tuning with modest computational resources and access to relevant data.

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• arXiv stat.APOct 19

  A Pitfall in the Evaluation of Gene Perturbation Models

  George Panagopoulos, Saman Omidi, Tsz Pan Tong, Jun Pang

  Gene perturbation models aim to predict transcriptional responses to unseen genetic interventions, but comparisons rely on heterogeneous evaluation metrics and differentially-expressed (DE) gene subsets. We investigate the consequences of these choices using eight methods across six single-gene perturbation datasets under a unified evaluation protocol. Varying the number of top DE genes reveals substantial instability in Precision-based rankings, with the winning method changing $86.7\%$ of the time, while rankings based on the rest of the metrics remain comparatively stable. Investigating this discrepancy exposes that repeating a single predicted expression profile across cell-level rows, a standard practice for many methods, can inflate significance estimates and produce excessively large predicted significant-DE sets. Specifically we found that $67.1\%$ of tested perturbation--gene pairs pass the significance threshold despite some of them having minuscule effects. We derive an inflation factor showing that replicated predictions can amplify the standardized Mann--Whitney statistic even after correction for tied ranks, without adding independent information. This artifact…

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• arXiv cs.AIOct 19

  REFLEX: RNA Ensemble Generation via Flexibility-Calibrated Stochastic Bridge

  Wanli Ma, Tianmeng Hu, Ke Li

  RNA molecules often function through multiple experimentally observed conformational states. A central challenge is to capture ensemble diversity without sacrificing structural fidelity: samples may collapse toward averaged representative structures or drift into unsupported conformational regions. We introduce REFLEX (RNA Ensemble generation calibrated by FLEXibility), a sequence-conditioned generator for RNA backbone-frame ensembles based on a heteroscedastic stochastic bridge on SE(3). During training, experimental B-factors calibrate residue-wise bridge widths, exposing each observed conformer through local perturbation neighborhoods with residue-specific scales while keeping constrained regions sharper. A learned flexibility condition guides the bridge-field network to recover target conformer-specific frames from these calibrated noisy states. At inference, REFLEX uses only the input sequence, requiring no MSA-subsampling heuristics. On a multi-conformer RNA benchmark, REFLEX achieves the best precision-recall trade-off for ensemble coverage across evaluation thresholds, while recovery-stress ablations indicate gains in target-frame recovery under stronger perturbations.

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• arXiv cs.LGOct 19

  ProtGlycanDock: Towards Accurate Protein-Glycan Docking with Tailored Dataset, Benchmark and Model

  Minghao Xu, Jiaze Song, Jinyu Wang, Wentao Zhang

  Performing accurate protein-glycan docking is critical to understanding protein-glycan interactions which govern many biological processes. However, this important task is hampered by the lack of tailored datasets, benchmarks and models for protein-glycan docking. To fill this blank, we first curate a standard benchmark ProtGlycanDock for training and evaluating protein-glycan docking models under both protein and glycan generalization settings. On this benchmark, we evaluate ten models in three categories, physics-based docking methods, machine-learning-based docking models and molecular structure prediction models. To obtain more precise binding poses, we further propose two finetuning techniques to inject the knowledge of glycan conformations into a general-purpose molecular structure prediction model. These two techniques respectively augment model inputs with glycan topological features and refine glycan binding pose with a glycan energy loss. Benchmark results show the superiority of AlphaFold 3 among existing methods, and the two proposed finetuning techniques can be well combined to achieve a state-of-the-art model for protein-glycan docking. Also, we perform stratified…

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• arXiv cs.AIOct 19

  HyperTaxa: Multiscale Genome Representations for Generalized Microbial Taxonomic Inference

  Akash Rao, Sushim Gupta, Vishalini Ramnath, Akhilesh Ramachandran, Sathyanarayanan Aakur

  Reliable microbial taxonomic inference is challenged by the rapid growth of newly sequenced organisms and incomplete reference coverage. While alignment- and database-driven tools remain essential for reference-backed identification, they are not designed for learned inference over species absent from genome-level training. We introduce HyperTaxa, a taxonomy-aligned representation learning framework for open-set microbial taxonomic inference. HyperTaxa encodes whole genomes as multiscale hyperspectral k-mer transition fields and aligns these representations to a taxonomy-derived semantic space using a two-stage Node2Vec-to-MDS procedure that combines local graph structure with global hierarchical distance preservation. The resulting space supports zero-shot inference over species excluded from genome-level training but represented in the taxonomy, generalized zero-shot inference over seen and unseen species, and cascaded genus-to-species prediction. Across benchmark and large-scale disjoint-species evaluations, HyperTaxa improves taxonomic prediction over pseudo-image and transformer-graph baselines, with the strongest gains at higher taxonomic ranks. Ablations further show that…

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• arXiv cs.LGOct 19

  PRISM: Prior Relational Information for Self-supervised Modeling to Enhance Solubility OOD Generalization

  Xinyi Chen, Jiahuan Pang, Titus Chima, Paul Weng, Wendong Wang

  Solubility depends on intermolecular interactions between solutes and solvents, and is central to drug discovery, chemical and materials process engineering. Its prediction requires out-of-distribution (OOD) generalization to unseen solutes, solvents, and solvent mixtures, where supervised methods suffer from data scarcity, and existing self-supervised methods do not explicitly learn chemically meaningful relations. Learning chemically meaningful relational information without labels can alleviate data scarcity and improve OOD generalization, but remains challenging. We introduce Prior Relational Information for Self-supervised Modeling (PRISM) and apply it to solubility OOD generalization. PRISM is a label-free pretraining framework that converts expert-defined chemical priors into relational teachers. For solubility prediction, it trains four encoders to preserve the population-level relational information from priors capturing hydrophobic, electrostatic, polarizability, and substructural effects, using Kullback-Leibler (KL) divergence to match distance-based neighborhood distributions during pretraining. Across scaffold, solute, and solvent OOD settings, PRISM matches or…

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• arXiv cs.LGOct 18

  M-JEPA: Predictive Self-Supervised Learning for Molecular Graphs with Scaffold-Shift Evaluation on Tox21

  Karthik Iyer, Nasser Sabar

  Self-supervised molecular representation learning is increasingly used to improve transfer on small, label-limited property prediction tasks, yet commonly used contrastive objectives can be sensitive to view construction and are often evaluated with protocols that report only discrimination. We adapt Joint Embedding Predictive Architectures (JEPAs) to molecular graphs by masking chemically coherent connected subgraphs and training a context encoder to regress the masked target embedding produced by an exponential-moving-average (EMA) teacher. To evaluate predictive self-supervision under realistic distribution shift, we introduce a leakage-resistant, compute-matched three-phase protocol: (i) an 80-run objective screening on ESOL with fixed compute budgets, (ii) JEPA-only refinement of masking and augmentation choices, and (iii) per-assay Tox21 evaluation under Bemis-Murcko scaffold splits with joint discrimination-reliability analysis and attribution diagnostics. Under matched compute, M-JEPA achieves substantially lower ESOL proxy RMSE than a compute-matched InfoNCE baseline (mean RMSE 2.12 vs 3.75; mean paired dRMSE 1.61; 95% bootstrap CI [1.52, 1.72]; Wilcoxon p=2.4e-4) and…

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• arXiv cs.LGOct 18

  Synergy-Aware Residual Flow Matching for Single-Cell Perturbation Prediction

  Jingrui Wu, Wangyun Dan

  Predicting single-cell responses to genetic and chemical perturbations is important for understanding regulatory mechanisms and prioritizing therapeutic interventions. Existing methods have made progress by modeling perturbation-conditioned expression shifts with neural networks, graph priors, foundation-model representations, or distributional generative models. However, combinatorial perturbation prediction remains challenging because much of the response can be explained by additive single-perturbation effects, while the biologically informative signal often lies in a smaller non-additive residual induced by perturbation interactions. Directly generating the full post-perturbation expression profile may therefore allocate substantial capacity to the dominant additive component and underemphasize synergy-specific structure. To address this issue, we propose \textbf{SynGeneFlow}, a synergy-aware flow matching framework that anchors the source distribution at an additive prior and learns a residual flow toward the true perturbed state. SynGeneFlow further incorporates perturbation-conditioned gene interaction modeling, where a static gene-gene mask provides biological structure…

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• arXiv cs.AIOct 17

  ReTRACE: Feedback-Guided LLM Agent in a Chemistry Harness for Retrosynthesis Planning

  Jinxiang Xie, Yijian Zhang, Qingyuan Yi, Jianyi Wang, Hao Dong

  Computer-aided retrosynthesis has advanced through single-step prediction, tree search and route scoring, but complex targets still require judgement over the whole route, where stereochemistry, functional-group compatibility, cost and greenness interact. Here we present \textbf{\mbox{ReTRACE}} (\textbf{RE}trosynthesis with \textbf{T}ool-orchestrated \textbf{R}easoning \textbf{A}nd \textbf{C}ontext-aware \textbf{E}vidence), an agent that places a large language model (LLM) in a chemistry harness that integrates molecular tools, complementary single-step prediction engines, a purchasable starting-material library, a route memory and a multi-criterion route evaluator. Routes are judged by a new metric that combines programmatic checks with adversarial LLM review, and its verdicts are compared with a synthetic chemist's. The agent learns continually from evaluator feedback during search, diagnosing weak routes and backtracking to revise them. With Claude Opus 4.8, at least one of the top 10 routes proposed by ReTRACE passed the audit for 87.4\%, 95.0\% and 86.7\% of targets on the three benchmarks. Two prospective wet-lab syntheses show that ReTRACE route proposals can be converted…

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• arXiv cs.LGOct 17

  TopoCompile: Molecular Generation with Exact Global Count Constraints

  Xiang Wu, Rong-Hua Li, Quanqing Xu, Kangfei Zhao, Guoren Wang

  Molecular generation designs novel molecules with desired structures and properties. Global count constraints specify molecular size, elemental composition, and ring content without prescribing detailed structure. Property-conditioned generators steer generation toward such targets but do not guarantee exact satisfaction. We introduce TopoCompile, which combines an autoregressive component-tree generator with a dynamic-programming compiler for supported component-additive integer counts. TopoCompile represents molecules as trees of intact ring systems and individual atoms, making each supported count additive over components. At each step, an autoregressive Transformer scores component and attachment actions, while the compiler masks actions with no target-satisfying completion. Within the fixed component vocabulary and typed attachment rules, constrained decoding guarantees exact equality for supported non-negative, component-additive integer counts. Applied at inference time, these checks let the same trained generator support different targets and count combinations without retraining. Across four benchmarks, TopoCompile achieves 100% Exact-valid yield for Common and Rare…

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• arXiv cs.LGOct 17

  Generative Retrieval for Reverse Target Fishing with a Proteome-Scale Benchmark

  Zhichao Deng, Haichuan Tan, Xin Hong, Huaizhi Wang, Tao Huang +2

  Reverse target fishing identifies protein targets for a query molecule and is central to drug discovery and repurposing. Discriminative approaches adapted from virtual screening face sparse, long-tailed associations and missing-not-at-random measurements: treating unrecorded pairs as negatives can suppress genuine targets. We reformulate the task as generative retrieval and introduce GenFish. Residual vector quantization converts frozen protein language model features into shared semantic identifiers. Given a molecular fingerprint, GenFish autoregressively models codes conditioned on the query and preceding code, ranking proteins by identifier likelihood without explicitly labeling unrecorded pairs as negatives. We introduce ProTargetBench, the first proteome-scale benchmark for reverse target fishing to jointly support measured-panel discrimination and full-catalogue recovery of experimentally recorded positives. Covering 20,431 UniProt-reviewed human proteins, it integrates curated bioactivity evidence and distinguishes experimental inactivity from unmeasured associations. On 198 held-out molecules, GenFish achieves higher mean performance across all three full-catalogue…

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• Reliable geometric reasoning from protein structures1 paper raises it · 2 address it

  Frontier models excel at metadata lookup but struggle with numeric geometry tasks, which are critical for structural biology.

  • ProteinGeoBench: Frontier Structural-Biology Agents Are Fluent at Lookup but Lost in Geometryraises
  • Does Learning Protein Folding Generalize to Broader Reasoning?addresses
  • Learning Latent Protein Languages for Autoregressive Generationaddresses
• Effective integration of biological foundation model inputs1 paper raises it · 1 addresses it

  Biological reasoning models often ignore foundation model inputs, relying instead on text, which limits their accuracy and interpretability.

  • When Do Biological Reasoning Models Use Their Biological Inputs?raises
  • Does Learning Protein Folding Generalize to Broader Reasoning?addresses
• Scalable and robust protein sequence and structure generation1 paper raises it · 2 address it

  Autoregressive models for protein generation are weak, and current representations lack contextual semantics or efficient discrete encodings.

  • Learning Latent Protein Languages for Autoregressive Generationraises · addresses
  • recAMPLIFY: Large-Scale Pretraining of Recursive Protein Language Modelsaddresses
• Durable and selective pretraining data filtering1 paper raises it · 1 addresses it

  Filtering pretraining data can degrade performance on specific domains, but fine-tuning can easily undo these effects, limiting its long-term utility.

  • The Effectiveness and Durability of Pretraining Data Filtering in Protein Language Modelsraises · addresses
• Stable evaluation metrics for gene perturbation models1 paper raises it · 0 address it

  Heterogeneous metrics and DE gene subsets lead to unstable rankings, undermining fair comparisons across methods.

  • A Pitfall in the Evaluation of Gene Perturbation Modelsraises

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