Zhifeng Gao

Gengmo Zhou, Zhifeng Gao, Zhewei Wei et al. · microsoft-research

Molecular conformation generation (MCG) is a fundamental and important problem in drug discovery. Many traditional methods have been developed to solve the MCG problem, such as systematic searching, model-building, random searching, distance geometry, molecular dynamics, Monte Carlo methods, etc. However, they have some limitations depending on the molecular structures. Recently, there are plenty of deep learning based MCG methods, which claim they largely outperform the traditional methods. However, to our surprise, we design a simple and cheap algorithm (parameter-free) based on the traditional methods and find it is comparable to or even outperforms deep learning based MCG methods in the widely used GEOM-QM9 and GEOM-Drugs benchmarks. In particular, our design algorithm is simply the clustering of the RDKIT-generated conformations. We hope our findings can help the community to revise the deep learning methods for MCG. The code of the proposed algorithm could be found at https://gist.github.com/ZhouGengmo/5b565f51adafcd911c0bc115b2ef027c.

Shuqi Lu, Zhifeng Gao, Di He et al. · microsoft-research

Recent developments in deep learning have made remarkable progress in speeding up the prediction of quantum chemical (QC) properties by removing the need for expensive electronic structure calculations like density functional theory. However, previous methods learned from 1D SMILES sequences or 2D molecular graphs failed to achieve high accuracy as QC properties primarily depend on the 3D equilibrium conformations optimized by electronic structure methods, far different from the sequence-type and graph-type data. In this paper, we propose a novel approach called Uni-Mol+ to tackle this challenge. Uni-Mol+ first generates a raw 3D molecule conformation from inexpensive methods such as RDKit. Then, the raw conformation is iteratively updated to its target DFT equilibrium conformation using neural networks, and the learned conformation will be used to predict the QC properties. To effectively learn this update process towards the equilibrium conformation, we introduce a two-track Transformer model backbone and train it with the QC property prediction task. We also design a novel approach to guide the model's training process. Our extensive benchmarking results demonstrate that the proposed Uni-Mol+ significantly improves the accuracy of QC property prediction in various datasets. We have made the code and model publicly available at \url{https://github.com/dptech-corp/Uni-Mol}.

Yuejiang Yu, Shuqi Lu, Zhifeng Gao et al. · microsoft-research

Molecular docking, given a ligand molecule and a ligand binding site (called ``pocket'') on a protein, predicting the binding mode of the protein-ligand complex, is a widely used technique in drug design. Many deep learning models have been developed for molecular docking, while most existing deep learning models perform docking on the whole protein, rather than on a given pocket as the traditional molecular docking approaches, which does not match common needs. What's more, they claim to perform better than traditional molecular docking, but the approach of comparison is not fair, since traditional methods are not designed for docking on the whole protein without a given pocket. In this paper, we design a series of experiments to examine the actual performance of these deep learning models and traditional methods. For a fair comparison, we decompose the docking on the whole protein into two steps, pocket searching and docking on a given pocket, and build pipelines to evaluate traditional methods and deep learning methods respectively. We find that deep learning models are actually good at pocket searching, but traditional methods are better than deep learning models at docking on given pockets. Overall, our work explicitly reveals some potential problems in current deep learning models for molecular docking and provides several suggestions for future works.

Zhifeng Gao, Xiaohong Ji, Guojiang Zhao et al. · microsoft-research

Recently deep learning based quantitative structure-activity relationship (QSAR) models has shown surpassing performance than traditional methods for property prediction tasks in drug discovery. However, most DL based QSAR models are restricted to limited labeled data to achieve better performance, and also are sensitive to model scale and hyper-parameters. In this paper, we propose Uni-QSAR, a powerful Auto-ML tool for molecule property prediction tasks. Uni-QSAR combines molecular representation learning (MRL) of 1D sequential tokens, 2D topology graphs, and 3D conformers with pretraining models to leverage rich representation from large-scale unlabeled data. Without any manual fine-tuning or model selection, Uni-QSAR outperforms SOTA in 21/22 tasks of the Therapeutic Data Commons (TDC) benchmark under designed parallel workflow, with an average performance improvement of 6.09\%. Furthermore, we demonstrate the practical usefulness of Uni-QSAR in drug discovery domains.

Lin Yao, Ruihan Xu, Zhifeng Gao et al. · microsoft-research

The central problem in cryo-electron microscopy (cryo-EM) is to recover the 3D structure from noisy 2D projection images which requires estimating the missing projection angles (poses). Recent methods attempted to solve the 3D reconstruction problem with the autoencoder architecture, which suffers from the latent vector space sampling problem and frequently produces suboptimal pose inferences and inferior 3D reconstructions. Here we present an improved autoencoder architecture called ACE (Asymmetric Complementary autoEncoder), based on which we designed the ACE-EM method for cryo-EM 3D reconstructions. Compared to previous methods, ACE-EM reached higher pose space coverage within the same training time and boosted the reconstruction performance regardless of the choice of decoders. With this method, the Nyquist resolution (highest possible resolution) was reached for 3D reconstructions of both simulated and experimental cryo-EM datasets. Furthermore, ACE-EM is the only amortized inference method that reached the Nyquist resolution.

Yanyi Su, Hongshuai Wang, Zhifeng Gao et al.

Olfaction lies at the intersection of chemical structure, neural encoding, and linguistic perception, yet existing representation methods fail to fully capture this pathway. Current approaches typically model only isolated segments of the olfactory pathway, overlooking the complete chain from molecule to receptors to linguistic descriptions. Such fragmentation yields learned embeddings that lack both biological grounding and semantic interpretability. We propose NOSE (Neural Olfactory-Semantic Embedding), a representation learning framework that aligns three modalities along the olfactory pathway: molecular structure, receptor sequence, and natural language description. Rather than simply fusing these signals, we decouple their contributions via orthogonal constraints, preserving the unique encoded information of each modality. To address the sparsity of olfactory language, we introduce a weak positive sample strategy to calibrate semantic similarity, preventing erroneous repulsion of similar odors in the feature space. Extensive experiments demonstrate that NOSE achieves state-of-the-art (SOTA) performance and excellent zero-shot generalization, confirming the strong alignment between its representation space and human olfactory intuition.Code and data are available at https://github.com/Xianyusyy/NOSE

Zichen Wen, Boxue Yang, Shuang Chen et al.

We present Innovator-VL, a scientific multimodal large language model designed to advance understanding and reasoning across diverse scientific domains while maintaining excellent performance on general vision tasks. Contrary to the trend of relying on massive domain-specific pretraining and opaque pipelines, our work demonstrates that principled training design and transparent methodology can yield strong scientific intelligence with substantially reduced data requirements. (i) First, we provide a fully transparent, end-to-end reproducible training pipeline, covering data collection, cleaning, preprocessing, supervised fine-tuning, reinforcement learning, and evaluation, along with detailed optimization recipes. This facilitates systematic extension by the community. (ii) Second, Innovator-VL exhibits remarkable data efficiency, achieving competitive performance on various scientific tasks using fewer than five million curated samples without large-scale pretraining. These results highlight that effective reasoning can be achieved through principled data selection rather than indiscriminate scaling. (iii) Third, Innovator-VL demonstrates strong generalization, achieving competitive performance on general vision, multimodal reasoning, and scientific benchmarks. This indicates that scientific alignment can be integrated into a unified model without compromising general-purpose capabilities. Our practices suggest that efficient, reproducible, and high-performing scientific multimodal models can be built even without large-scale data, providing a practical foundation for future research.

Fanmeng Wang, Haotian Liu, Guojiang Zhao et al.

While Chain-of-Thought (CoT) significantly enhances the performance of Large Language Models (LLMs), explicit reasoning chains introduce substantial computational redundancy. Recent latent reasoning methods attempt to mitigate this by compressing reasoning processes into latent space, but often suffer from severe performance degradation due to the lack of appropriate compression guidance. In this study, we propose Rendered CoT-Guided variational Latent Reasoning (ReGuLaR), a simple yet novel latent learning paradigm resolving this issue. Fundamentally, we formulate latent reasoning within the Variational Auto-Encoding (VAE) framework, sampling the current latent reasoning state from the posterior distribution conditioned on previous ones. Specifically, when learning this variational latent reasoning model, we render explicit reasoning chains as images, from which we extract dense visual-semantic representations to regularize the posterior distribution, thereby achieving efficient compression with minimal information loss. Extensive experiments demonstrate that ReGuLaR significantly outperforms existing latent reasoning methods across both computational efficiency and reasoning effectiveness, and even surpasses CoT through multi-modal reasoning, providing a new and insightful solution to latent reasoning. Code: https://github.com/FanmengWang/ReGuLaR.

Yutang Ge, Guojiang Zhao, Sihang Li et al.

Designing proteins that satisfy natural language functional requirements is a central goal in protein engineering. A straightforward baseline is to fine-tune generic instruction-tuned LLMs as direct text-to-sequence generators, but this is data- and compute-hungry. With limited supervision, LLMs can produce coherent plans in text yet fail to reliably realize them as sequences. This plan-execute gap motivates ProtoCycle, an agentic framework for protein design that uses LLMs primarily to drive a multi-round, feedback-driven decision cycle. ProtoCycle couples an LLM planner with a lightweight tool environment designed to emulate the iterative workflow of human protein engineering and uses LLM-driven reflection on tool feedback to revise plans. Trained with supervised trajectories and online reinforcement learning, ProtoCycle achieves strong language alignment while maintaining competitive foldability, and ablations show that reflection substantially improves sequence quality.

Hengxing Cai, Xiaochen Cai, Junhan Chang et al.

Recent breakthroughs in Large Language Models (LLMs) have revolutionized scientific literature analysis. However, existing benchmarks fail to adequately evaluate the proficiency of LLMs in this domain, particularly in scenarios requiring higher-level abilities beyond mere memorization and the handling of multimodal data. In response to this gap, we introduce SciAssess, a benchmark specifically designed for the comprehensive evaluation of LLMs in scientific literature analysis. It aims to thoroughly assess the efficacy of LLMs by evaluating their capabilities in Memorization (L1), Comprehension (L2), and Analysis \& Reasoning (L3). It encompasses a variety of tasks drawn from diverse scientific fields, including biology, chemistry, material, and medicine. To ensure the reliability of SciAssess, rigorous quality control measures have been implemented, ensuring accuracy, anonymization, and compliance with copyright standards. SciAssess evaluates 11 LLMs, highlighting their strengths and areas for improvement. We hope this evaluation supports the ongoing development of LLM applications in scientific literature analysis. SciAssess and its resources are available at \url{https://github.com/sci-assess/SciAssess}.

Gengmo Zhou, Zhen Wang, Feng Yu et al.

Virtual Screening is an essential technique in the early phases of drug discovery, aimed at identifying promising drug candidates from vast molecular libraries. Recently, ligand-based virtual screening has garnered significant attention due to its efficacy in conducting extensive database screenings without relying on specific protein-binding site information. Obtaining binding affinity data for complexes is highly expensive, resulting in a limited amount of available data that covers a relatively small chemical space. Moreover, these datasets contain a significant amount of inconsistent noise. It is challenging to identify an inductive bias that consistently maintains the integrity of molecular activity during data augmentation. To tackle these challenges, we propose S-MolSearch, the first framework to our knowledge, that leverages molecular 3D information and affinity information in semi-supervised contrastive learning for ligand-based virtual screening. Drawing on the principles of inverse optimal transport, S-MolSearch efficiently processes both labeled and unlabeled data, training molecular structural encoders while generating soft labels for the unlabeled data. This design allows S-MolSearch to adaptively utilize unlabeled data within the learning process. Empirically, S-MolSearch demonstrates superior performance on widely-used benchmarks LIT-PCBA and DUD-E. It surpasses both structure-based and ligand-based virtual screening methods for AUROC, BEDROC and EF.

Yi Xiong, Liang Xiong, Xiaohong Ji et al.

Molecular property optimization is central to drug discovery, yet many deep learning methods rely on black-box scoring and offer limited control over scaffold preservation, often producing unstable or biologically implausible edits. While large language models (LLMs) are promising molecular generators, optimization remains constrained by the lack of chemistry-grounded preference supervision and principled data curation. We introduce \textbf{Scaffold-Conditioned Preference Triplets (SCPT)}, a pipeline that constructs similarity-constrained triplets $\langle\text{scaffold}, \text{better}, \text{worse}\rangle$ via scaffold alignment and chemistry-driven filters for validity, synthesizability, and meaningful property gains. Using these preferences, we align a pretrained molecular LLM as a conditional editor, enabling property-improving edits that retain the scaffold. Across single- and multi-objective benchmarks, SCPT improves optimization success and property gains while maintaining higher scaffold similarity than competitive baselines. Compared with representative non-LLM molecular optimization methods, SCPT-trained LLMs are better suited to scaffold-constrained and multi-objective optimization. In addition, models trained on single-property and two-property supervision generalize effectively to three-property tasks, indicating promising extrapolative generalization under limited higher-order supervision. SCPT also provides controllable data-construction knobs that yield a predictable similarity-gain frontier, enabling systematic adaptation to diverse optimization regimes.

Linfeng Zhang, Siheng Chen, Yuzhu Cai et al.

AI agents are emerging as a practical way to run multi-step scientific workflows that interleave reasoning with tool use and verification, pointing to a shift from isolated AI-assisted steps toward \emph{agentic science at scale}. This shift is increasingly feasible, as scientific tools and models can be invoked through stable interfaces and verified with recorded execution traces, and increasingly necessary, as AI accelerates scientific output and stresses the peer-review and publication pipeline, raising the bar for traceability and credible evaluation. However, scaling agentic science remains difficult: workflows are hard to observe and reproduce; many tools and laboratory systems are not agent-ready; execution is hard to trace and govern; and prototype AI Scientist systems are often bespoke, limiting reuse and systematic improvement from real workflow signals. We argue that scaling agentic science requires an infrastructure-and-ecosystem approach, instantiated in Bohrium+SciMaster. Bohrium acts as a managed, traceable hub for AI4S assets -- akin to a HuggingFace of AI for Science -- that turns diverse scientific data, software, compute, and laboratory systems into agent-ready capabilities. SciMaster orchestrates these capabilities into long-horizon scientific workflows, on which scientific agents can be composed and executed. Between infrastructure and orchestration, a \emph{scientific intelligence substrate} organizes reusable models, knowledge, and components into executable building blocks for workflow reasoning and action, enabling composition, auditability, and improvement through use. We demonstrate this stack with eleven representative master agents in real workflows, achieving orders-of-magnitude reductions in end-to-end scientific cycle time and generating execution-grounded signals from real workloads at multi-million scale.

Boshen Zeng, Sian Chen, Xinxin Liu et al.

Advancements in lithium battery technology heavily rely on the design and engineering of electrolytes. However, current schemes for molecular design and recipe optimization of electrolytes lack an effective computational-experimental closed loop and often fall short in accurately predicting diverse electrolyte formulation properties. In this work, we introduce Uni-ELF, a novel multi-level representation learning framework to advance electrolyte design. Our approach involves two-stage pretraining: reconstructing three-dimensional molecular structures at the molecular level using the Uni-Mol model, and predicting statistical structural properties (e.g., radial distribution functions) from molecular dynamics simulations at the mixture level. Through this comprehensive pretraining, Uni-ELF is able to capture intricate molecular and mixture-level information, which significantly enhances its predictive capability. As a result, Uni-ELF substantially outperforms state-of-the-art methods in predicting both molecular properties (e.g., melting point, boiling point, synthesizability) and formulation properties (e.g., conductivity, Coulombic efficiency). Moreover, Uni-ELF can be seamlessly integrated into an automatic experimental design workflow. We believe this innovative framework will pave the way for automated AI-based electrolyte design and engineering.

Eric Alcaide, Zhifeng Gao, Guolin Ke et al.

In recent years, machine learning (ML) methods have emerged as promising alternatives for molecular docking, offering the potential for high accuracy without incurring prohibitive computational costs. However, recent studies have indicated that these ML models may overfit to quantitative metrics while neglecting the physical constraints inherent in the problem. In this work, we present Uni-Mol Docking V2, which demonstrates a remarkable improvement in performance, accurately predicting the binding poses of 77+% of ligands in the PoseBusters benchmark with an RMSD value of less than 2.0 Å, and 75+% passing all quality checks. This represents a significant increase from the 62% achieved by the previous Uni-Mol Docking model. Notably, our Uni-Mol Docking approach generates chemically accurate predictions, circumventing issues such as chirality inversions and steric clashes that have plagued previous ML models. Furthermore, we observe enhanced performance in terms of high-quality predictions (RMSD values of less than 1.0 Å and 1.5 Å) and physical soundness when Uni-Mol Docking is combined with more physics-based methods like Uni-Dock. Our results represent a significant advancement in the application of artificial intelligence for scientific research, adopting a holistic approach to ligand docking that is well-suited for industrial applications in virtual screening and drug design. The code, data and service for Uni-Mol Docking are publicly available for use and further development in https://github.com/dptech-corp/Uni-Mol.

Gengmo Zhou, Feng Yu, Wenda Wang et al.

Enzymes are crucial catalysts that enable a wide range of biochemical reactions. Efficiently identifying specific enzymes from vast protein libraries is essential for advancing biocatalysis. Traditional computational methods for enzyme screening and retrieval are time-consuming and resource-intensive. Recently, deep learning approaches have shown promise. However, these methods focus solely on the interaction between enzymes and reactions, overlooking the inherent hierarchical relationships within each domain. To address these limitations, we introduce FGW-CLIP, a novel contrastive learning framework based on optimizing the fused Gromov-Wasserstein distance. FGW-CLIP incorporates multiple alignments, including inter-domain alignment between reactions and enzymes and intra-domain alignment within enzymes and reactions. By introducing a tailored regularization term, our method minimizes the Gromov-Wasserstein distance between enzyme and reaction spaces, which enhances information integration across these domains. Extensive evaluations demonstrate the superiority of FGW-CLIP in challenging enzyme-reaction tasks. On the widely-used EnzymeMap benchmark, FGW-CLIP achieves state-of-the-art performance in enzyme virtual screening, as measured by BEDROC and EF metrics. Moreover, FGW-CLIP consistently outperforms across all three splits of ReactZyme, the largest enzyme-reaction benchmark, demonstrating robust generalization to novel enzymes and reactions. These results position FGW-CLIP as a promising framework for enzyme discovery in complex biochemical settings, with strong adaptability across diverse screening scenarios.

Yutang Ge, Yaning Cui, Hanzheng Li et al.

Intelligent spectroscopy serves as a pivotal element in AI-driven closed-loop scientific discovery, functioning as the critical bridge between matter structure and artificial intelligence. However, conventional expert-dependent spectral interpretation encounters substantial hurdles, including susceptibility to human bias and error, dependence on limited specialized expertise, and variability across interpreters. To address these challenges, we propose SpecXMaster, an intelligent framework leveraging Agentic Reinforcement Learning (RL) for NMR molecular spectral interpretation. SpecXMaster enables automated extraction of multiplicity information from both 1H and 13C spectra directly from raw FID (free induction decay) data. This end-to-end pipeline enables fully automated interpretation of NMR spectra into chemical structures. It demonstrates superior performance across multiple public NMR interpretation benchmarks and has been refined through iterative evaluations by professional chemical spectroscopists. We believe that SpecXMaster, as a novel methodological paradigm for spectral interpretation, will have a profound impact on the organic chemistry community.

Mingjun Xu, Jinhan Dong, Jue Hou et al.

Multimodal document retrieval systems enable information access across text, images, and layouts, benefiting various domains like document-based question answering, report analysis, and interactive content summarization. Rerankers improve retrieval precision by reordering retrieved candidates. However, current multimodal reranking methods remain underexplored, with significant room for improvement in both training strategies and overall effectiveness. Moreover, the lack of explicit reasoning makes it difficult to analyze and optimize these methods further. In this paper, We propose MM-R5, a MultiModal Reasoning-Enhanced ReRanker via Reinforcement Learning for Document Retrieval, aiming to provide a more effective and reliable solution for multimodal reranking tasks. MM-R5 is trained in two stages: supervised fine-tuning (SFT) and reinforcement learning (RL). In the SFT stage, we focus on improving instruction-following and guiding the model to generate complete and high-quality reasoning chains. To support this, we introduce a novel data construction strategy that produces rich, high-quality reasoning data. In the RL stage, we design a task-specific reward framework, including a reranking reward tailored for multimodal candidates and a composite template-based reward to further refine reasoning quality. We conduct extensive experiments on MMDocIR, a challenging public benchmark spanning multiple domains. MM-R5 achieves state-of-the-art performance on most metrics and delivers comparable results to much larger models on the remaining ones. Moreover, compared to the best retrieval-only method, MM-R5 improves recall@1 by over 4%. These results validate the effectiveness of our reasoning-enhanced training pipeline. Our code is available at https://github.com/i2vec/MM-R5 .

Haitao Lin, Guojiang Zhao, Odin Zhang et al.

Structure-based drug design (SBDD) aims to generate potential drugs that can bind to a target protein and is greatly expedited by the aid of AI techniques in generative models. However, a lack of systematic understanding persists due to the diverse settings, complex implementation, difficult reproducibility, and task singularity. Firstly, the absence of standardization can lead to unfair comparisons and inconclusive insights. To address this dilemma, we propose CBGBench, a comprehensive benchmark for SBDD, that unifies the task as a generative heterogeneous graph completion, analogous to fill-in-the-blank of the 3D complex binding graph. By categorizing existing methods based on their attributes, CBGBench facilitates a modular and extensible framework that implements various cutting-edge methods. Secondly, a single task on \textit{de novo} molecule generation can hardly reflect their capabilities. To broaden the scope, we have adapted these models to a range of tasks essential in drug design, which are considered sub-tasks within the graph fill-in-the-blank tasks. These tasks include the generative designation of \textit{de novo} molecules, linkers, fragments, scaffolds, and sidechains, all conditioned on the structures of protein pockets. Our evaluations are conducted with fairness, encompassing comprehensive perspectives on interaction, chemical properties, geometry authenticity, and substructure validity. We further provide the pre-trained versions of the state-of-the-art models and deep insights with analysis from empirical studies. The codebase for CBGBench is publicly accessible at \url{https://github.com/Edapinenut/CBGBench}.

Qingsi Lai, Fanjie Xu, Lin Yao et al.

Powder X-ray diffraction (PXRD) is a prevalent technique in materials characterization. While the analysis of PXRD often requires extensive human manual intervention, and most automated method only achieved at coarse-grained level. The more difficult and important task of fine-grained crystal structure prediction from PXRD remains unaddressed. This study introduces XtalNet, the first equivariant deep generative model for end-to-end crystal structure prediction from PXRD. Unlike previous crystal structure prediction methods that rely solely on composition, XtalNet leverages PXRD as an additional condition, eliminating ambiguity and enabling the generation of complex organic structures with up to 400 atoms in the unit cell. XtalNet comprises two modules: a Contrastive PXRD-Crystal Pretraining (CPCP) module that aligns PXRD space with crystal structure space, and a Conditional Crystal Structure Generation (CCSG) module that generates candidate crystal structures conditioned on PXRD patterns. Evaluation on two MOF datasets (hMOF-100 and hMOF-400) demonstrates XtalNet's effectiveness. XtalNet achieves a top-10 Match Rate of 90.2% and 79% for hMOF-100 and hMOF-400 in conditional crystal structure prediction task, respectively. XtalNet enables the direct prediction of crystal structures from experimental measurements, eliminating the need for manual intervention and external databases. This opens up new possibilities for automated crystal structure determination and the accelerated discovery of novel materials.

Yaorui Shi, Sihang Li, Taiyan Zhang et al.

Automated drug discovery offers significant potential for accelerating the development of novel therapeutics by substituting labor-intensive human workflows with machine-driven processes. However, molecules generated by artificial intelligence may unintentionally infringe on existing patents, posing legal and financial risks that impede the full automation of drug discovery pipelines. This paper introduces PatentFinder, a novel multi-agent and tool-enhanced intelligence system that can accurately and comprehensively evaluate small molecules for patent infringement. PatentFinder features five specialized agents that collaboratively analyze patent claims and molecular structures with heuristic and model-based tools, generating interpretable infringement reports. To support systematic evaluation, we curate MolPatent-240, a benchmark dataset tailored for patent infringement assessment algorithms. On this benchmark, PatentFinder outperforms baseline methods that rely solely on large language models or specialized chemical tools, achieving a 13.8% improvement in F1-score and a 12% increase in accuracy. Additionally, PatentFinder autonomously generates detailed and interpretable patent infringement reports, showcasing enhanced accuracy and improved interpretability. The high accuracy and interpretability of PatentFinder make it a valuable and reliable tool for automating patent infringement assessments, offering a practical solution for integrating patent protection analysis into the drug discovery pipeline.

Fanmeng Wang, Wentao Guo, Qi Ou et al.

Polymer conformation generation is a critical task that enables atomic-level studies of diverse polymer materials. While significant advances have been made in designing conformation generation methods for small molecules and proteins, these methods struggle to generate polymer conformations due to their unique structural characteristics. Meanwhile, the scarcity of polymer conformation datasets further limits the progress, making this important area largely unexplored. In this work, we propose PolyConf, a pioneering tailored polymer conformation generation method that leverages hierarchical generative models to unlock new possibilities. Specifically, we decompose the polymer conformation into a series of local conformations (i.e., the conformations of its repeating units), generating these local conformations through an autoregressive model, and then generating their orientation transformations via a diffusion model to assemble them into the complete polymer conformation. Moreover, we develop the first benchmark with a high-quality polymer conformation dataset derived from molecular dynamics simulations to boost related research in this area. The comprehensive evaluation demonstrates that PolyConf consistently outperforms existing conformation generation methods, thus facilitating advancements in polymer modeling and simulation.

Haitao Lin, Odin Zhang, Jia Xu et al.

The affinity and specificity of protein-molecule binding directly impact functional outcomes, uncovering the mechanisms underlying biological regulation and signal transduction. Most deep-learning-based prediction approaches focus on structures of atoms or fragments. However, quantum chemical properties, such as electronic structures, are the key to unveiling interaction patterns but remain largely underexplored. To bridge this gap, we propose ECBind, a method for tokenizing electron cloud signals into quantized embeddings, enabling their integration into downstream tasks such as binding affinity prediction. By incorporating electron densities, ECBind helps uncover binding modes that cannot be fully represented by atom-level models. Specifically, to remove the redundancy inherent in electron cloud signals, a structure-aware transformer and hierarchical codebooks encode 3D binding sites enriched with electron structures into tokens. These tokenized codes are then used for specific tasks with labels. To extend its applicability to a wider range of scenarios, we utilize knowledge distillation to develop an electron-cloud-agnostic prediction model. Experimentally, ECBind demonstrates state-of-the-art performance across multiple tasks, achieving improvements of 6.42\% and 15.58\% in per-structure Pearson and Spearman correlation coefficients, respectively.

Guojiang Zhao, Sihang Li, Zixiang Lu et al.

Large Language Models(LLMs) have demonstrated remarkable performance across various domains, yet their capabilities in molecular reasoning remain insufficiently explored. Current approaches tend to rely heavily on general-purpose prompting, which lacks domain-specific molecular semantics, while those that use fine-tuning strategies often face challenges with interpretability and reasoning depth. To address these issues, we introduce MolReasoner, a two-stage framework designed to transition LLMs from memorization towards chemical reasoning. First, we propose Mol-SFT, which initializes the model's reasoning abilities via synthetic Chain-of-Thought(CoT) samples generated by GPT-4o and verified for chemical accuracy. Subsequently, Mol-RL applies reinforcement learning with specialized reward functions designed explicitly to align chemical structures with linguistic descriptions, thereby enhancing molecular reasoning capabilities. Our approach notably enhances interpretability, improving the model 's molecular understanding and enabling better generalization. Extensive experiments demonstrate that MolReasoner outperforms existing methods, and marking a significant shift from memorization-based outputs to robust chemical reasoning.

Shuqi Lu, Haowei Lin, Lin Yao et al. · pku

3D structure modeling is essential across scales, enabling applications from fluid simulation and 3D reconstruction to protein folding and molecular docking. Yet, despite shared 3D spatial patterns, current approaches remain fragmented, with models narrowly specialized for specific domains and unable to generalize across tasks or scales. We propose Uni-3DAR, a unified autoregressive framework for cross-scale 3D generation and understanding. At its core is a coarse-to-fine tokenizer based on octree data structures, which compresses diverse 3D structures into compact 1D token sequences. We further propose a two-level subtree compression strategy, which reduces the octree token sequence by up to 8x. To address the challenge of dynamically varying token positions introduced by compression, we introduce a masked next-token prediction strategy that ensures accurate positional modeling, significantly boosting model performance. Extensive experiments across multiple 3D generation and understanding tasks, including small molecules, proteins, polymers, crystals, and macroscopic 3D objects, validate its effectiveness and versatility. Notably, Uni-3DAR surpasses previous state-of-the-art diffusion models by a substantial margin, achieving up to 256\% relative improvement while delivering inference speeds up to 21.8x faster.

Yun Hao, Che Fan, Beilin Ye et al.

Deep generative models hold great promise for inverse materials design, yet their efficiency and accuracy remain constrained by data scarcity and model architecture. Here, we introduce AlloyGAN, a closed-loop framework that integrates Large Language Model (LLM)-assisted text mining with Conditional Generative Adversarial Networks (CGANs) to enhance data diversity and improve inverse design. Taking alloy discovery as a case study, AlloyGAN systematically refines material candidates through iterative screening and experimental validation. For metallic glasses, the framework predicts thermodynamic properties with discrepancies of less than 8% from experiments, demonstrating its robustness. By bridging generative AI with domain knowledge and validation workflows, AlloyGAN offers a scalable approach to accelerate the discovery of materials with tailored properties, paving the way for broader applications in materials science.

Hengxing Cai, Xiaochen Cai, Shuwen Yang et al.

In scientific research and its application, scientific literature analysis is crucial as it allows researchers to build on the work of others. However, the fast growth of scientific knowledge has led to a massive increase in scholarly articles, making in-depth literature analysis increasingly challenging and time-consuming. The emergence of Large Language Models (LLMs) has offered a new way to address this challenge. Known for their strong abilities in summarizing texts, LLMs are seen as a potential tool to improve the analysis of scientific literature. However, existing LLMs have their own limits. Scientific literature often includes a wide range of multimodal elements, such as tables, charts, and molecule, which are hard for text-focused LLMs to understand and analyze. This issue points to the urgent need for new solutions that can fully understand and analyze multimodal content in scientific literature. To answer this demand, we present \textbf{Uni-SMART} (Universal Science Multimodal Analysis and Research Transformer), an innovative model designed for in-depth understanding of multimodal scientific literature. Through rigorous quantitative evaluation across several domains, Uni-SMART demonstrates superior performance over other text-focused LLMs. Furthermore, our exploration extends to practical applications, including patent infringement detection and nuanced analysis of charts. These applications not only highlight Uni-SMART's adaptability but also its potential to revolutionize how we interact with scientific literature.

Shuqi Lu, Xiaohong Ji, Bohang Zhang et al.

Molecular pretrained representations (MPR) has emerged as a powerful approach for addressing the challenge of limited supervised data in applications such as drug discovery and material design. While early MPR methods relied on 1D sequences and 2D graphs, recent advancements have incorporated 3D conformational information to capture rich atomic interactions. However, these prior models treat molecules merely as discrete atom sets, overlooking the space surrounding them. We argue from a physical perspective that only modeling these discrete points is insufficient. We first present a simple yet insightful observation: naively adding randomly sampled virtual points beyond atoms can surprisingly enhance MPR performance. In light of this, we propose a principled framework that incorporates the entire 3D space spanned by molecules. We implement the framework via a novel Transformer-based architecture, dubbed SpaceFormer, with three key components: (1) grid-based space discretization; (2) grid sampling/merging; and (3) efficient 3D positional encoding. Extensive experiments show that SpaceFormer significantly outperforms previous 3D MPR models across various downstream tasks with limited data, validating the benefit of leveraging the additional 3D space beyond atoms in MPR models.

Hengxing Cai, Jinhan Dong, Jingjun Tan et al.

Unmanned Aerial Vehicle (UAV) Vision-and-Language Navigation (VLN) is vital for applications such as disaster response, logistics delivery, and urban inspection. However, existing methods often struggle with insufficient multimodal fusion, weak generalization, and poor interpretability. To address these challenges, we propose FlightGPT, a novel UAV VLN framework built upon Vision-Language Models (VLMs) with powerful multimodal perception capabilities. We design a two-stage training pipeline: first, Supervised Fine-Tuning (SFT) using high-quality demonstrations to improve initialization and structured reasoning; then, Group Relative Policy Optimization (GRPO) algorithm, guided by a composite reward that considers goal accuracy, reasoning quality, and format compliance, to enhance generalization and adaptability. Furthermore, FlightGPT introduces a Chain-of-Thought (CoT)-based reasoning mechanism to improve decision interpretability. Extensive experiments on the city-scale dataset CityNav demonstrate that FlightGPT achieves state-of-the-art performance across all scenarios, with a 9.22\% higher success rate than the strongest baseline in unseen environments. Our implementation is publicly available.

Zhen Wang, Zhifeng Gao, Guolin Ke

Test-time scaling has been shown to substantially improve large language models' (LLMs) mathematical reasoning. However, for a large portion of mathematical corpora, especially theorem proving, RLVR's scalability is limited: intermediate reasoning is crucial, while final answers are difficult to directly and reliably verify. Meanwhile, token-level SFT often degenerates into rote memorization rather than inducing longer chains of thought. Inspired by BERT's self-supervised tasks, we propose MR-RLVR (Masked-and-Reordered RLVR), which constructs process-level self-supervised rewards via "masked-then-fill" and "step reordering" to extract learnable signals from intermediate reasoning. Our training pipeline comprises two stages: we first perform self-supervised training on sampled mathematical calculation and proof data; we then conduct RLVR fine-tuning on mathematical calculation datasets where only outcomes are verifiable. We implement MR-RLVR on Qwen2.5-3B and DeepSeek-R1-Distill-Qwen-1.5B, and evaluate on AIME24, AIME25, AMC23, and MATH500. Under a fixed sampling and decoding budget, MR-RLVR achieves average relative gains over the original RLVR of +9.86% Pass@1, +5.27% Pass@5, and +4.00% Pass@8. These results indicate that incorporating process-aware self-supervised signals can effectively enhance RLVR's scalability and performance in only outcome-verifiable settings.

Fanmeng Wang, Shan Mei, Wentao Guo et al.

Polymers, macromolecules formed from covalently bonded monomers, underpin countless technologies and are indispensable to modern life. While deep learning is advancing polymer science, existing methods typically represent the whole polymer solely through monomer-level descriptors, overlooking the global structural information inherent in polymer conformations, which ultimately limits their practical performance. Moreover, this field still lacks a universal foundation model that can effectively support diverse downstream tasks, thereby severely constraining progress. To address these challenges, we introduce PolyConFM, the first polymer foundation model that unifies polymer modeling and design through conformation-centric generative pretraining. Recognizing that each polymer conformation can be decomposed into a sequence of local conformations (i.e., those of its repeating units), we pretrain PolyConFM under the conditional generation paradigm, reconstructing these local conformations via masked autoregressive (MAR) modeling and further generating their orientation transformations to recover the corresponding polymer conformation. Besides, we construct the first high-quality polymer conformation dataset via molecular dynamics simulations to mitigate data sparsity, thereby enabling conformation-centric pretraining. Experiments demonstrate that PolyConFM consistently outperforms representative task-specific methods on diverse downstream tasks, equipping polymer science with a universal and powerful tool.

Lirong Wu, Junjie Wang, Zhifeng Gao et al.

Organic reaction, the foundation of modern chemical industry, is crucial for new material development and drug discovery. However, deciphering reaction mechanisms and modeling multi-molecular relationships remain formidable challenges due to the complexity of molecular dynamics. While several state-of-the-art models like Uni-Mol2 have revolutionized single-molecular representation learning, their extension to multi-molecular systems, where chemical reactions inherently occur, has been underexplored. This paper introduces Uni-Mol3, a novel deep learning framework that employs a hierarchical pipeline for multi-molecular reaction modeling. At its core, Uni-Mol3 adopts a multi-scale molecular tokenizer (Mol-Tokenizer) that encodes 3D structures of molecules and other features into discrete tokens, creating a 3D-aware molecular language. The framework innovatively combines two pre-training stages: molecular pre-training to learn the molecular grammars and reaction pre-training to capture fundamental reaction principles, forming a progressive learning paradigm from single- to multi-molecular systems. With prompt-aware downstream fine-tuning, Uni-Mol3 demonstrates exceptional performance in diverse organic reaction tasks and supports multi-task prediction with strong generalizability. Experimental results across 10 datasets spanning 4 downstream tasks show that Uni-Mol3 outperforms existing methods, validating its effectiveness in modeling complex organic reactions. This work not only ushers in an alternative paradigm for multi-molecular computational modeling but also charts a course for intelligent organic reaction by bridging molecular representation with reaction mechanism understanding.

Haitao Lin, Junjie Wang, Zhifeng Gao et al.

The essence of a chemical reaction lies in the redistribution and reorganization of electrons, which is often manifested through electron transfer or the migration of electron pairs. These changes are inherently discrete and abrupt in the physical world, such as alterations in the charge states of atoms or the formation and breaking of chemical bonds. To model the transition of states, we propose SynBridge, a bidirectional flow-based generative model to achieve multi-task reaction prediction. By leveraging a graph-to-graph transformer network architecture and discrete flow bridges between any two discrete distributions, SynBridge captures bidirectional chemical transformations between graphs of reactants and products through the bonds' and atoms' discrete states. We further demonstrate the effectiveness of our method through extensive experiments on three benchmark datasets (USPTO-50K, USPTO-MIT, Pistachio), achieving state-of-the-art performance in both forward and retrosynthesis tasks. Our ablation studies and noise scheduling analysis reveal the benefits of structured diffusion over discrete spaces for reaction prediction.

Jiaxi Zhuang, Kangning Li, Jue Hou et al.

Extracting molecular structure-activity relationships (SARs) from scientific literature and patents is essential for drug discovery and materials research. However, this task remains challenging due to heterogeneous document formats and limitations of existing methods. Specifically, rule-based approaches relying on rigid templates fail to generalize across diverse document layouts, while general-purpose multimodal large language models (MLLMs) lack sufficient accuracy and reliability for specialized tasks, such as layout detection and optical chemical structure recognition (OCSR). To address these challenges, we introduce DocSAR-200, a rigorously annotated benchmark of 200 scientific documents designed specifically for evaluating SAR extraction methods. Additionally, we propose Doc2SAR, a novel synergistic framework that integrates domain-specific tools with MLLMs enhanced via supervised fine-tuning (SFT). Extensive experiments demonstrate that Doc2SAR achieves state-of-the-art performance across various document types, significantly outperforming leading end-to-end baselines. Specifically, Doc2SAR attains an overall Table Recall of 80.78% on DocSAR-200, exceeding end2end GPT-4o by 51.48%. Furthermore, Doc2SAR demonstrates practical usability through efficient inference and is accompanied by a web app.

Lirong Wu, Yunfan Liu, Haitao Lin et al.

The proteins that exist today have been optimized over billions of years of natural evolution, during which nature creates random mutations and selects them. The discovery of functionally promising mutations is challenged by the limited evolutionary accessible regions, i.e., only a small region on the fitness landscape is beneficial. There have been numerous priors used to constrain protein evolution to regions of landscapes with high-fitness variants, among which the change in binding free energy (DDG) of protein complexes upon mutations is one of the most commonly used priors. However, the huge mutation space poses two challenges: (1) how to improve the efficiency of DDG prediction for fast mutation screening; and (2) how to explain mutation preferences and efficiently explore accessible evolutionary regions. To address these challenges, we propose a lightweight DDG predictor (Light-DDG), which adopts a structure-aware Transformer as the backbone and enhances it by knowledge distilled from existing powerful but computationally heavy DDG predictors. Additionally, we augmented, annotated, and released a large-scale dataset containing millions of mutation data for pre-training Light-DDG. We find that such a simple yet effective Light-DDG can serve as a good unsupervised antibody optimizer and explainer. For the target antibody, we propose a novel Mutation Explainer to learn mutation preferences, which accounts for the marginal benefit of each mutation per residue. To further explore accessible evolutionary regions, we conduct preference-guided antibody optimization and evaluate antibody candidates quickly using Light-DDG to identify desirable mutations.

Xiaohong Ji, Zhen Wang, Zhifeng Gao et al.

In recent years, pretraining models have made significant advancements in the fields of natural language processing (NLP), computer vision (CV), and life sciences. The significant advancements in NLP and CV are predominantly driven by the expansion of model parameters and data size, a phenomenon now recognized as the scaling laws. However, research exploring scaling law in molecular pretraining models remains unexplored. In this work, we present Uni-Mol2 , an innovative molecular pretraining model that leverages a two-track transformer to effectively integrate features at the atomic level, graph level, and geometry structure level. Along with this, we systematically investigate the scaling law within molecular pretraining models, characterizing the power-law correlations between validation loss and model size, dataset size, and computational resources. Consequently, we successfully scale Uni-Mol2 to 1.1 billion parameters through pretraining on 800 million conformations, making it the largest molecular pretraining model to date. Extensive experiments show consistent improvement in the downstream tasks as the model size grows. The Uni-Mol2 with 1.1B parameters also outperforms existing methods, achieving an average 27% improvement on the QM9 and 14% on COMPAS-1D dataset.

Fanmeng Wang, Wentao Guo, Minjie Cheng et al.

Polymers are high-molecular-weight compounds constructed by the covalent bonding of numerous identical or similar monomers so that their 3D structures are complex yet exhibit unignorable regularity. Typically, the properties of a polymer, such as plasticity, conductivity, bio-compatibility, and so on, are highly correlated with its 3D structure. However, existing polymer property prediction methods heavily rely on the information learned from polymer SMILES sequences (P-SMILES strings) while ignoring crucial 3D structural information, resulting in sub-optimal performance. In this work, we propose MMPolymer, a novel multimodal multitask pretraining framework incorporating polymer 1D sequential and 3D structural information to encourage downstream polymer property prediction tasks. Besides, considering the scarcity of polymer 3D data, we further introduce the "Star Substitution" strategy to extract 3D structural information effectively. During pretraining, in addition to predicting masked tokens and recovering clear 3D coordinates, MMPolymer achieves the cross-modal alignment of latent representations. Then we further fine-tune the pretrained MMPolymer for downstream polymer property prediction tasks in the supervised learning paradigm. Experiments show that MMPolymer achieves state-of-the-art performance in downstream property prediction tasks. Moreover, given the pretrained MMPolymer, utilizing merely a single modality in the fine-tuning phase can also outperform existing methods, showcasing the exceptional capability of MMPolymer in polymer feature extraction and utilization.

Yunbo Wang, Haixu Wu, Jianjin Zhang et al.

The predictive learning of spatiotemporal sequences aims to generate future images by learning from the historical context, where the visual dynamics are believed to have modular structures that can be learned with compositional subsystems. This paper models these structures by presenting PredRNN, a new recurrent network, in which a pair of memory cells are explicitly decoupled, operate in nearly independent transition manners, and finally form unified representations of the complex environment. Concretely, besides the original memory cell of LSTM, this network is featured by a zigzag memory flow that propagates in both bottom-up and top-down directions across all layers, enabling the learned visual dynamics at different levels of RNNs to communicate. It also leverages a memory decoupling loss to keep the memory cells from learning redundant features. We further propose a new curriculum learning strategy to force PredRNN to learn long-term dynamics from context frames, which can be generalized to most sequence-to-sequence models. We provide detailed ablation studies to verify the effectiveness of each component. Our approach is shown to obtain highly competitive results on five datasets for both action-free and action-conditioned predictive learning scenarios.

Chao Du, Zhifeng Gao, Shuo Yuan et al.

Modern online advertising systems inevitably rely on personalization methods, such as click-through rate (CTR) prediction. Recent progress in CTR prediction enjoys the rich representation capabilities of deep learning and achieves great success in large-scale industrial applications. However, these methods can suffer from lack of exploration. Another line of prior work addresses the exploration-exploitation trade-off problem with contextual bandit methods, which are recently less studied in the industry due to the difficulty in extending their flexibility with deep models. In this paper, we propose a novel Deep Uncertainty-Aware Learning (DUAL) method to learn CTR models based on Gaussian processes, which can provide predictive uncertainty estimations while maintaining the flexibility of deep neural networks. DUAL can be easily implemented on existing models and deployed in real-time systems with minimal extra computational overhead. By linking the predictive uncertainty estimation ability of DUAL to well-known bandit algorithms, we further present DUAL-based Ad-ranking strategies to boost up long-term utilities such as the social welfare in advertising systems. Experimental results on several public datasets demonstrate the effectiveness of our methods. Remarkably, an online A/B test deployed in the Alibaba display advertising platform shows an 8.2% social welfare improvement and an 8.0% revenue lift.

Zhining Liu, Wei Cao, Zhifeng Gao et al.

Many real-world applications reveal difficulties in learning classifiers from imbalanced data. The rising big data era has been witnessing more classification tasks with large-scale but extremely imbalance and low-quality datasets. Most of existing learning methods suffer from poor performance or low computation efficiency under such a scenario. To tackle this problem, we conduct deep investigations into the nature of class imbalance, which reveals that not only the disproportion between classes, but also other difficulties embedded in the nature of data, especially, noises and class overlapping, prevent us from learning effective classifiers. Taking those factors into consideration, we propose a novel framework for imbalance classification that aims to generate a strong ensemble by self-paced harmonizing data hardness via under-sampling. Extensive experiments have shown that this new framework, while being very computationally efficient, can lead to robust performance even under highly overlapping classes and extremely skewed distribution. Note that, our methods can be easily adapted to most of existing learning methods (e.g., C4.5, SVM, GBDT and Neural Network) to boost their performance on imbalanced data.

Bowen Wu, Nan Jiang, Zhifeng Gao et al.

Recent advances in sequence-to-sequence learning reveal a purely data-driven approach to the response generation task. Despite its diverse applications, existing neural models are prone to producing short and generic replies, making it infeasible to tackle open-domain challenges. In this research, we analyze this critical issue in light of the model's optimization goal and the specific characteristics of the human-to-human dialog corpus. By decomposing the black box into parts, a detailed analysis of the probability limit was conducted to reveal the reason behind these universal replies. Based on these analyses, we propose a max-margin ranking regularization term to avoid the models leaning to these replies. Finally, empirical experiments on case studies and benchmarks with several metrics validate this approach.

Yunbo Wang, Zhifeng Gao, Mingsheng Long et al.

We present PredRNN++, an improved recurrent network for video predictive learning. In pursuit of a greater spatiotemporal modeling capability, our approach increases the transition depth between adjacent states by leveraging a novel recurrent unit, which is named Causal LSTM for re-organizing the spatial and temporal memories in a cascaded mechanism. However, there is still a dilemma in video predictive learning: increasingly deep-in-time models have been designed for capturing complex variations, while introducing more difficulties in the gradient back-propagation. To alleviate this undesirable effect, we propose a Gradient Highway architecture, which provides alternative shorter routes for gradient flows from outputs back to long-range inputs. This architecture works seamlessly with causal LSTMs, enabling PredRNN++ to capture short-term and long-term dependencies adaptively. We assess our model on both synthetic and real video datasets, showing its ability to ease the vanishing gradient problem and yield state-of-the-art prediction results even in a difficult objects occlusion scenario.

Kele Xu, Xi Liu, Hengxing Cai et al.

During the last decades, the number of new full-reference image quality assessment algorithms has been increasing drastically. Yet, despite of the remarkable progress that has been made, the medical ultrasound image similarity measurement remains largely unsolved due to a high level of speckle noise contamination. Potential applications of the ultrasound image similarity measurement seem evident in several aspects. To name a few, ultrasound imaging quality assessment, abnormal function region detection, etc. In this paper, a comparative study was made on full-reference image quality assessment methods for ultrasound image visual structural similarity measure. Moreover, based on the image similarity index, a generic ultrasound motion tracking re-initialization framework is given in this work. The experiments are conducted on synthetic data and real-ultrasound liver data and the results demonstrate that, with proposed similarity-based tracking re-initialization, the mean error of landmarks tracking can be decreased from 2 mm to about 1.5 mm in the ultrasound liver sequence.