Wei-Ying Ma

TMLR Journal 2026 Journal Article

ACDiT: Interpolating Autoregressive Conditional Modeling and Diffusion Transformer

• Jinyi Hu
• Shengding Hu
• Yuxuan Song
• Yufei Huang
• Mingxuan Wang
• Hao Zhou
• Zhiyuan Liu
• Wei-Ying Ma

Autoregressive and diffusion models have achieved remarkable progress in language models and visual generation, respectively. We present ACDiT, a novel Autoregressive blockwise Conditional Diffusion Transformer, that innovatively combines autoregressive and diffusion paradigms for continuous visual information. By introducing a block-wise autoregressive unit, ACDiT offers a flexible interpolation between token-wise autoregression and full-sequence diffusion, bypassing the limitations of discrete tokenization. The generation of each block is formulated as a conditional diffusion process, conditioned on prior blocks. ACDiT is easy to implement, as simple as applying a specially designed Skip-Causal Attention Mask on the standard diffusion transformer during training. During inference, the process iterates between diffusion denoising and autoregressive decoding that can make full use of KV-Cache. We validate the effectiveness of ACDiT on image, video, and text generation and show that ACDiT performs best among all autoregressive baselines under similar model scales on visual generation tasks. We also demonstrate that, benefiting from autoregressive modeling, pretrained ACDiT can be transferred in visual understanding tasks despite being trained with the generative objective. The analysis of the trade-off between autoregressive and diffusion demonstrates the potential of ACDiT to be used in long-horizon visual generation tasks. We hope that ACDiT offers a novel perspective on visual autoregressive generation and sheds light on new avenues for unified models.

AAAI Conference 2026 Conference Paper

Learning Protein–Ligand Binding in Hyperbolic Space

• Jianhui Wang
• Wenyu Zhu
• Bowen Gao
• Xin Hong
• Ya-Qin Zhang
• Wei-Ying Ma
• Yanyan Lan

Protein-ligand binding prediction is central to virtual screening and affinity ranking, two fundamental tasks in drug discovery. While recent retrieval-based methods embed ligands and protein pockets into Euclidean space for similarity-based search, the geometry of Euclidean embeddings often fails to capture the hierarchical structure and fine-grained affinity variations intrinsic to molecular interactions. In this work, we propose HypSeek, a hyperbolic representation learning framework that embeds ligands, protein pockets, and sequences into Lorentz-model hyperbolic space. By leveraging the exponential geometry and negative curvature of hyperbolic space, HypSeek enables expressive, affinity-sensitive embeddings that can effectively model both global activity and subtle functional differences–particularly in challenging cases such as activity cliffs, where structurally similar ligands exhibit large affinity gaps. Our model unifies virtual screening and affinity ranking in a single framework, introducing a protein-guided three-tower architecture to enhance representational structure. HypSeek improves early enrichment in virtual screening on DUD-E from 42.63 to 51.44 (+20.7%) and affinity ranking correlation on JACS from 0.5774 to 0.7239 (+25.4%), demonstrating the benefits of hyperbolic geometry across both tasks and highlighting its potential as a powerful inductive bias for protein-ligand modeling.

AAAI Conference 2026 Conference Paper

S²Drug: Bridging Protein Sequence and 3D Structure in Contrastive Representation Learning for Virtual Screening

• Bowei He
• Bowen Gao
• Yankai Chen
• Yanyan Lan
• Chen Ma
• Philip S. Yu
• Ya-Qin Zhang
• Wei-Ying Ma

Virtual screening (VS) is an essential task in drug discovery, focusing on the identification of small-molecule ligands that bind to specific protein pockets. Existing deep learning methods, from early regression models to recent contrastive learning approaches, primarily rely on structural data while overlooking protein sequences, which are more accessible and can enhance generalizability. However, directly integrating protein sequences poses challenges due to the redundancy and noise in large-scale protein-ligand datasets. To address these limitations, we propose S²Drug, a two-stage framework that explicitly incorporates protein Sequence information and 3D Structure context in protein-ligand contrastive representation learning. In the first stage, we perform protein sequence pretraining on ChemBL using an ESM2-based backbone, combined with a tailored data sampling strategy to reduce redundancy and noise on both protein and ligand sides. In the second stage, we fine-tune on PDBBind by fusing sequence and structure information through a residue-level gating module, while introducing an auxiliary binding site prediction task. This auxiliary task guides the model to accurately localize binding residues within the protein sequence and capture their 3D spatial arrangement, thereby refining protein-ligand matching. Across multiple benchmarks, S²Drug consistently improves virtual screening performance and achieves strong results on binding site prediction, demonstrating the value of bridging sequence and structure in contrastive learning.

ICLR Conference 2025 Conference Paper

A Periodic Bayesian Flow for Material Generation

• Hanlin Wu
• Yuxuan Song
• Jingjing Gong
• Ziyao Cao
• Yawen Ouyang
• Jianbing Zhang
• Hao Zhou 0012
• Wei-Ying Ma

Generative modeling of crystal data distribution is an important yet challenging task due to the unique periodic physical symmetry of crystals. Diffusion-based methods have shown early promise in modeling crystal distribution. More recently, Bayesian Flow Networks were introduced to aggregate noisy latent variables, resulting in a variance-reduced parameter space that has been shown to be advantageous for modeling Euclidean data distributions with structural constraints (Song, et al.,2023). Inspired by this, we seek to unlock its potential for modeling variables located in non-Euclidean manifolds e.g. those within crystal structures, by overcoming challenging theoretical issues. We introduce CrysBFN, a novel crystal generation method by proposing a periodic Bayesian flow, which essentially differs from the original Gaussian-based BFN by exhibiting non-monotonic entropy dynamics. To successfully realize the concept of periodic Bayesian flow, CrysBFN integrates a new entropy conditioning mechanism and empirically demonstrates its significance compared to time-conditioning. Extensive experiments over both crystal ab initio generation and crystal structure prediction tasks demonstrate the superiority of CrysBFN, which consistently achieves new state-of-the-art on all benchmarks. Surprisingly, we found that CrysBFN enjoys a significant improvement in sampling efficiency, e.g., 200x speedup (10 v.s. 2000 steps network forwards) compared with previous Diffusion-based methods on MP-20 dataset.

NeurIPS Conference 2025 Conference Paper

AANet: Virtual Screening under Structural Uncertainty via Alignment and Aggregation

• Wenyu Zhu
• Jianhui Wang
• Bowen Gao
• Yinjun Jia
• Haichuan Tan
• Ya-Qin Zhang
• Wei-Ying Ma
• Yanyan Lan

Virtual screening (VS) is a critical component of modern drug discovery, yet most existing methods—whether physics-based or deep learning-based—are developed around holo protein structures with known ligand-bound pockets. Consequently, their performance degrades significantly on apo or predicted structures such as those from AlphaFold2, which are more representative of real-world early-stage drug discovery, where pocket information is often missing. In this paper, we introduce an alignment-and-aggregation framework to enable accurate virtual screening under structural uncertainty. Our method comprises two core components: (1) a tri-modal contrastive learning module that aligns representations of the ligand, the holo pocket, and cavities detected from structures, thereby enhancing robustness to pocket localization error; and (2) a cross-attention based adapter for dynamically aggregating candidate binding sites, enabling the model to learn from activity data even without precise pocket annotations. We evaluated our method on a newly curated benchmark of apo structures, where it significantly outperforms state-of-the-art methods in blind apo setting, improving the early enrichment factor (EF1\%) from 11. 75 to 37. 19. Notably, it also maintains strong performance on holo structures. These results demonstrate the promise of our approach in advancing first-in-class drug discovery, particularly in scenarios lacking experimentally resolved protein-ligand complexes. Our implementation is publicly available at https: //github. com/Wiley-Z/AANet.

NeurIPS Conference 2025 Conference Paper

Accelerating 3D Molecule Generative Models with Trajectory Diagnosis

• Zhilong Zhang
• Yuxuan Song
• Yichun Wang
• Jingjing Gong
• Hanlin Wu
• Dongzhan Zhou
• Hao Zhou
• Wei-Ying Ma

Geometric molecule generative models have found expanding applications across various scientific domains, but their generation inefficiency has become a critical bottleneck. Through a systematic investigation of the generative trajectory, we discover a unique challenge for molecule geometric graph generation: generative models require determining the permutation order of atoms in the molecule before refining its atomic feature values. Based on this insight, we decompose the generation process into permutation phase and adjustment phase, and propose a geometric-informed prior and consistency parameter objective to accelerate each phase. Extensive experiments demonstrate that our approach achieves competitive performance with approximately 10 sampling steps, 7. 5 × faster than previous state-of-the-art models and approximately 100 × faster than diffusion-based models, offering a significant step towards scalable molecular generation.

NeurIPS Conference 2025 Conference Paper

CIDD: Collaborative Intelligence for Structure-Based Drug Design Empowered by LLMs

• Bowen Gao
• Yanwen Huang
• Yiqiao Liu
• Wenxuan Xie
• Bowei He
• Haichuan Tan
• Wei-Ying Ma
• Ya-Qin Zhang

Structure-guided molecular generation is pivotal in early-stage drug discovery, enabling the design of compounds tailored to specific protein targets. However, despite recent advances in 3D generative modeling, particularly in improving docking scores, these methods often produce rare and intrinsically irrational molecular structures that deviate from drug-like chemical space. To quantify this issue, we propose a novel metric, the Molecule Reasonable Ratio (MRR), which measures structural rationality and reveals a critical gap between existing models and real-world approved drugs. To address this, we introduce the Collaborative Intelligence Drug Design (CIDD) framework, the first approach to unify the 3D interaction modeling capabilities of generative models with the general knowledge and reasoning power of large language models (LLMs). By leveraging LLM-based Chain-of-Thought reasoning, CIDD generates molecules that not only bind effectively to protein pockets but also exhibit strong structural drug-likeness, rationality, and synthetic accessibility. On the CrossDocked2020 benchmark, CIDD consistently improves drug-likeness metrics, including QED, SA, and MRR, across different base generative models, while maintaining competitive binding affinity. Notably, it raises the combined success rate (balancing drug-likeness and binding) from 15. 72% to 34. 59%, more than doubling previous results. These findings demonstrate the value of integrating knowledge reasoning with geometric generation to advance AI-driven drug design.

NeurIPS Conference 2025 Conference Paper

DAPO: An Open-Source LLM Reinforcement Learning System at Scale

• Qiying Yu
• Zheng Zhang
• Ruofei Zhu
• Yufeng Yuan
• Xiaochen Zuo
• Yu Yue
• Weinan Dai
• Tiantian Fan

Inference scaling empowers LLMs with unprecedented reasoning ability, with reinforcement learning as the core technique to elicit complex reasoning. However, key technical details of state-of-the-art reasoning LLMs are concealed (such as in OpenAI o1 blog and DeepSeek R1 technical report), thus the community still struggles to reproduce their RL training results. We propose the D ecoupled Clip and D ynamic s A mpling P olicy O ptimization ( DAPO ) algorithm, and fully open-source a state-of-the-art large-scale RL system that achieves 50 points on AIME 2024 using Qwen2. 5-32B base model. Unlike previous works that withhold training details, we introduce four key techniques of our algorithm that make large-scale LLM RL a success. In addition, we open-source our training code, which is built on the verl framework, along with a carefully curated and processed dataset. These components of our open-source system enhance reproducibility and support future research in large-scale LLM RL.

ICML Conference 2025 Conference Paper

Empower Structure-Based Molecule Optimization with Gradient Guided Bayesian Flow Networks

• Keyue Qiu
• Yuxuan Song
• Jie Yu
• Hongbo Ma
• Ziyao Cao
• Zhilong Zhang
• Yushuai Wu
• Mingyue Zheng

Structure-based molecule optimization (SBMO) aims to optimize molecules with both continuous coordinates and discrete types against protein targets. A promising direction is to exert gradient guidance on generative models given its remarkable success in images, but it is challenging to guide discrete data and risks inconsistencies between modalities. To this end, we leverage a continuous and differentiable space derived through Bayesian inference, presenting Molecule Joint Optimization (MolJO), the gradient-based SBMO framework that facilitates joint guidance signals across different modalities while preserving SE(3)-equivariance. We introduce a novel backward correction strategy that optimizes within a sliding window of the past histories, allowing for a seamless trade-off between explore-and-exploit during optimization. MolJO achieves state-of-the-art performance on CrossDocked2020 benchmark (Success Rate 51. 3%, Vina Dock -9. 05 and SA 0. 78), more than 4x improvement in Success Rate compared to the gradient-based counterpart, and 2x “Me-Better” Ratio as much as 3D baselines. Furthermore, we extend MolJO to a wide range of optimization settings, including multi-objective optimization and challenging tasks in drug design such as R-group optimization and scaffold hopping, further underscoring its versatility. Code is available at https: //github. com/AlgoMole/MolCRAFT.

NeurIPS Conference 2025 Conference Paper

FIGRDock: Fast Interaction-Guided Regression for Flexible Docking

• Shikun Feng
• Bicheng Lin
• Yuanhuan Mo
• Yuyan Ni
• Wenyu Zhu
• Bowen Gao
• Wei-Ying Ma
• Haitao Li

Flexible docking, which predicts the binding conformations of both proteins and small molecules by modeling their structural flexibility, plays a vital role in structure-based drug design. Although recent generative approaches, particularly diffusion-based models, have shown promising results, they require iterative sampling to generate candidate structures and depend on separate scoring functions for pose selection. This leads to an inefficient pipeline that is difficult to scale in real-world drug discovery workflows. To overcome these challenges, we introduce FIGRDock, a fast and accurate flexible docking framework that understands complicated interactions between molecules and proteins with a regression-based approach. FIGRDock leverages initial docking poses from conventional tools to distill interaction-aware distance patterns, which serve as explicit structural conditions to directly guide the prediction of the final protein-ligand complex via a regression model. This one-shot inference paradigm enables rapid and precise pose prediction without reliance on multi-step sampling or external scoring stages. Experimental results show that FIGRDock achieves up to 100× faster inference than diffusion-based docking methods, while consistently surpassing them in accuracy across standard benchmarks. These results suggest that FIGRDock has the potential to offer a scalable and efficient solution for flexible docking, advancing the pace of structure-based drug discovery.

NeurIPS Conference 2025 Conference Paper

Manipulating 3D Molecules in a Fixed-Dimensional E(3)-Equivariant Latent Space

• Zitao Chen
• Yinjun Jia
• Zitong Tian
• Wei-Ying Ma
• Yanyan Lan

Medicinal chemists often optimize drugs considering their 3D structures and designing structurally distinct molecules that retain key features, such as shapes, pharmacophores, or chemical properties. Previous deep learning approaches address this through supervised tasks like molecule inpainting or property-guided optimization. In this work, we propose a flexible zero-shot molecule manipulation method by navigating in a shared latent space of 3D molecules. We introduce a Variational AutoEncoder (VAE) for 3D molecules, named MolFLAE, which learns a fixed-dimensional, E(3)-equivariant latent space independent of atom counts. MolFLAE encodes 3D molecules using an E(3)-equivariant neural network into fixed number of latent nodes, distinguished by learned embeddings. The latent space is regularized, and molecular structures are reconstructed via a Bayesian Flow Network (BFN) conditioned on the encoder’s latent output. MolFLAE achieves competitive performance on standard unconditional 3D molecule generation benchmarks. Moreover, the latent space of MolFLAE enables zero-shot molecule manipulation, including atom number editing, structure reconstruction, and coordinated latent interpolation for both structure and properties. We further demonstrate our approach on a drug optimization task for the human glucocorticoid receptor, generating molecules with improved hydrophilicity while preserving key interactions, under computational evaluations. These results highlight the flexibility, robustness, and real-world utility of our method, opening new avenues for molecule editing and optimization.

NeurIPS Conference 2025 Conference Paper

MOF-BFN: Metal-Organic Frameworks Structure Prediction via Bayesian Flow Networks

• Rui Jiao
• Hanlin Wu
• Wenbing Huang
• Yuxuan Song
• Yawen Ouyang
• Yu Rong
• Tingyang Xu
• Pengju Wang

Metal-Organic Frameworks (MOFs) have attracted considerable attention due to their unique properties including high surface area and tunable porosity, and promising applications in catalysis, gas storage, and drug delivery. Structure prediction for MOFs is a challenging task, as these frameworks are intrinsically periodic and hierarchically organized, where the entire structure is assembled from building blocks like metal nodes and organic linkers. To address this, we introduce MOF-BFN, a novel generative model for MOF structure prediction based on Bayesian Flow Networks (BFNs). Given the local geometry of building blocks, MOF-BFN jointly predicts the lattice parameters, as well as the positions and orientations of all building blocks within the unit cell. In particular, the positions are modelled in the fractional coordinate system to naturally incorporate the periodicity. Meanwhile, the orientations are modeled as unit quaternions sampled from learned Bingham distributions via the proposed Bingham BFN, enabling effective orientation generation on the 4D unit hypersphere. Experimental results demonstrate that MOF-BFN achieves state-of-the-art performance across multiple tasks, including structure prediction, geometric property evaluation, and de novo generation, offering a promising tool for designing complex MOF materials.

ICML Conference 2025 Conference Paper

Piloting Structure-Based Drug Design via Modality-Specific Optimal Schedule

• Keyue Qiu
• Yuxuan Song
• Zhehuan Fan
• Peidong Liu
• Zhe Zhang
• Mingyue Zheng
• Hao Zhou 0012
• Wei-Ying Ma

Structure-Based Drug Design (SBDD) is crucial for identifying bioactive molecules. Recent deep generative models are faced with challenges in geometric structure modeling. A major bottleneck lies in the twisted probability path of multi-modalities—continuous 3D positions and discrete 2D topologies—which jointly determine molecular geometries. By establishing the fact that noise schedules decide the Variational Lower Bound (VLB) for the twisted probability path, we propose VLB-Optimal Scheduling (VOS) strategy in this under-explored area, which optimizes VLB as a path integral for SBDD. Our model effectively enhances molecular geometries and interaction modeling, achieving state-of-the-art PoseBusters passing rate of 95. 9% on CrossDock, more than 10% improvement upon strong baselines, while maintaining high affinities and robust intramolecular validity evaluated on held-out test set. Code is available at https: //github. com/AlgoMole/MolCRAFT.

NeurIPS Conference 2025 Conference Paper

Rationalized All-Atom Protein Design with Unified Multi-Modal Bayesian Flow

• Hanlin Wu
• Yuxuan Song
• Zhe Zhang
• Zhilong Zhang
• Hao Zhou
• Wei-Ying Ma
• Jingjing Liu

Designing functional proteins is a critical yet challenging problem due to the intricate interplay between backbone structures, sequences, and side-chains. Current approaches often decompose protein design into separate tasks, which can lead to accumulated errors, while recent efforts increasingly focus on all-atom protein design. However, we observe that existing all-atom generation approaches suffering from an information shortcut issue, where models inadvertently infer sequences from side-chain information, compromising their ability to accurately learn sequence distributions. To address this, we introduce a novel rationalized information flow strategy to eliminate the information shortcut. Furthermore, motivated by the advantages of Bayesian flows over differential equation–based methods, we propose the first Bayesian flow formulation for protein backbone orientations by recasting orientation modeling as an equivalent hyperspherical generation problem with antipodal symmetry. To validate, our method delivers consistently exceptional performance in both peptide and antibody design tasks.

ICLR Conference 2025 Conference Paper

Redefining the task of Bioactivity Prediction

• Yanwen Huang
• Bowen Gao
• Yinjun Jia
• Hongbo Ma
• Wei-Ying Ma
• Ya-Qin Zhang
• Yanyan Lan

Small molecules are vital to modern medicine, and accurately predicting their bioactivity against protein targets is crucial for therapeutic discovery and development. However, current machine learning models often rely on spurious features, leading to biased outcomes. Notably, a simple pocket-only baseline can achieve results comparable to, and sometimes better than, more complex models that incorporate both the protein pockets and the small molecules. Our analysis reveals that this phenomenon arises from insufficient training data and an improper evaluation process, which is typically conducted at the pocket level rather than the small molecule level. To address these issues, we redefine the bioactivity prediction task by introducing the SIU dataset-a million-scale Structural small molecule-protein Interaction dataset for Unbiased bioactivity prediction task, which is 50 times larger than the widely used PDBbind. The bioactivity labels in SIU are derived from wet experiments and organized by label types, ensuring greater accuracy and comparability. The complexes in SIU are constructed using a majority vote from three commonly used docking software programs, enhancing their reliability. Additionally, the structure of SIU allows for multiple small molecules to be associated with each protein pocket, enabling the redefinition of evaluation metrics like Pearson and Spearman correlations across different small molecules targeting the same protein pocket. Experimental results demonstrate that this new task provides a more challenging and meaningful benchmark for training and evaluating bioactivity prediction models, ultimately offering a more robust assessment of model performance.

ICLR Conference 2025 Conference Paper

Reframing Structure-Based Drug Design Model Evaluation via Metrics Correlated to Practical Needs

• Bowen Gao
• Haichuan Tan
• Yanwen Huang
• Minsi Ren
• Xiao Huang
• Wei-Ying Ma
• Ya-Qin Zhang
• Yanyan Lan

Recent advances in structure-based drug design (SBDD) have produced surprising results, with models often generating molecules that achieve better Vina docking scores than actual ligands. However, these results are frequently overly optimistic due to the limitations of docking score accuracy and the challenges of wet-lab validation. While generated molecules may demonstrate high QED (drug-likeness) and SA (synthetic accessibility) scores, they often lack true drug-like properties or synthesizability. To address these limitations, we propose a model-level evaluation framework that emphasizes practical metrics aligned with real-world applications. Inspired by recent findings on the utility of generated molecules in ligand-based virtual screening, our framework evaluates SBDD models by their ability to produce molecules that effectively retrieve active compounds from chemical libraries via similarity-based searches. This approach provides a direct indication of therapeutic potential, bridging the gap between theoretical performance and real-world utility. Our experiments reveal that while SBDD models may excel in theoretical metrics like Vina scores, they often fall short in these practical metrics. By introducing this new evaluation strategy, we aim to enhance the relevance and impact of SBDD models for pharmaceutical research and development.

NeurIPS Conference 2025 Conference Paper

Retro-R1: LLM-based Agentic Retrosynthesis

• Wei Liu
• Jiangtao Feng
• Hongli Yu
• Yuxuan Song
• Yuqiang Li
• Shufei Zhang
• Lei Bai
• Wei-Ying Ma

Retrosynthetic planning is a fundamental task in chemical discovery. Due to the vast combinatorial search space, identifying viable synthetic routes remains a significant challenge--even for expert chemists. Recent advances in Large Language Models (LLMs), particularly equipped with reinforcement learning, have demonstrated strong human-like reasoning and planning abilities, especially in mathematics and code problem solving. This raises a natural question: Can the reasoning capabilities of LLMs be harnessed to develop an AI chemist capable of learning effective policies for multi-step retrosynthesis? In this study, we introduce Retro-R1, a novel LLM-based retrosynthesis agent trained via reinforcement learning to design molecular synthesis pathways. Unlike prior approaches, which typically rely on single-turn, question-answering formats, Retro-R1 interacts dynamically with plug-in single-step retrosynthesis tools and learns from environmental feedback. Experimental results show that Retro-R1 achieves a 55. 79\% pass@1 success rate, surpassing the previous state of the art by 8. 95\%. Notably, Retro-R1 demonstrates strong generalization to out-of-domain test cases, where existing methods tend to fail despite their high in-domain performance. Our work marks a significant step toward equipping LLMs with advanced, chemist-like reasoning abilities, highlighting the promise of reinforcement learning for enabling data-efficient, generalizable, and sophisticated scientific problem-solving in LLM-based agents.

NeurIPS Conference 2025 Conference Paper

ShortListing Model: A Streamlined Simplex Diffusion for Discrete Variable Generation

• Yuxuan Song
• Zhe Zhang
• Yu Pei
• Jingjing Gong
• Qiying Yu
• Zheng Zhang
• Mingxuan Wang
• Hao Zhou

Generative modeling of discrete variables is challenging yet crucial for applications in natural language processing and biological sequence design. We introduce the Shortlisting Model (SLM), a novel simplex-based diffusion model inspired by progressive candidate pruning. SLM operates on simplex centroids, reducing generation complexity and enhancing scalability. Additionally, SLM incorporates a flexible implementation of classifier-free guidance, enhancing unconditional generation performance. Extensive experiments on DNA promoter and enhancer design, protein design, character-level and large-vocabulary language modeling demonstrate the competitive performance and strong potential of SLM. Our code can be found at https: //github. com/GenSI-THUAIR/SLM.

ICML Conference 2025 Conference Paper

Smooth Interpolation for Improved Discrete Graph Generative Models

• Yuxuan Song
• Juntong Shi
• Jingjing Gong
• Minkai Xu
• Stefano Ermon
• Hao Zhou 0012
• Wei-Ying Ma

Though typically represented by the discrete node and edge attributes, the graph topological information can be sufficiently captured by the graph spectrum in a continuous space. It is believed that incorporating the continuity of graph topological information into the generative process design could establish a superior paradigm for graph generative modeling. Motivated by such prior and recent advancements in the generative paradigm, we propose Graph Bayesian Flow Networks (GraphBFN) in this paper, a principled generative framework that designs an alternative generative process emphasizing the dynamics of topological information. Unlike recent discrete-diffusion-based methods, GraphBFNemploys the continuous counts derived from sampling infinite times from a categorical distribution as latent to facilitate a smooth decomposition of topological information, demonstrating enhanced effectiveness. To effectively realize the concept, we further develop an advanced sampling strategy and new time-scheduling techniques to overcome practical barriers and boost performance. Through extensive experimental validation on both generic graph and molecular graph generation tasks, GraphBFN could consistently achieve superior or competitive performance with significantly higher training and sampling efficiency.

ICLR Conference 2025 Conference Paper

Steering Protein Family Design through Profile Bayesian Flow

• Jingjing Gong
• Yu Pei
• Siyu Long
• Yuxuan Song
• Zhe Zhang
• Wenhao Huang 0001
• Ziyao Cao
• Shuyi Zhang

Protein family design emerges as a promising alternative by combining the advantages of de novo protein design and mutation-based directed evolution.In this paper, we propose ProfileBFN, the Profile Bayesian Flow Networks, for specifically generative modeling of protein families. ProfileBFN extends the discrete Bayesian Flow Network from an MSA profile perspective, which can be trained on single protein sequences by regarding it as a degenerate profile, thereby achieving efficient protein family design by avoiding large-scale MSA data construction and training. Empirical results show that ProfileBFN has a profound understanding of proteins. When generating diverse and novel family proteins, it can accurately capture the structural characteristics of the family. The enzyme produced by this method is more likely than the previous approach to have the corresponding function, offering better odds of generating diverse proteins with the desired functionality.

NeurIPS Conference 2025 Conference Paper

Straight-Line Diffusion Model for Efficient 3D Molecular Generation

• Yuyan Ni
• Shikun Feng
• Haohan Chi
• Bowen Zheng
• Huan-ang Gao
• Wei-Ying Ma
• Zhi-Ming Ma
• Yanyan Lan

Diffusion-based models have shown great promise in molecular generation but often require a large number of sampling steps to generate valid samples. In this paper, we introduce a novel Straight-Line Diffusion Model (SLDM) to tackle this problem, by formulating the diffusion process to follow a linear trajectory. The proposed process aligns well with the noise sensitivity characteristic of molecular structures and uniformly distributes reconstruction effort across the generative process, thus enhancing learning efficiency and efficacy. Consequently, SLDM achieves state-of-the-art performance on 3D molecule generation benchmarks, delivering a 100-fold improvement in sampling efficiency.

ICLR Conference 2025 Conference Paper

UniGEM: A Unified Approach to Generation and Property Prediction for Molecules

• Shikun Feng
• Yuyan Ni
• Yan Lu
• Zhiming Ma
• Wei-Ying Ma
• Yanyan Lan

Molecular generation and molecular property prediction are both crucial for drug discovery, but they are often developed independently. Inspired by recent studies, which demonstrate that diffusion model, a prominent generative approach, can learn meaningful data representations that enhance predictive tasks, we explore the potential for developing a unified generative model in the molecular domain that effectively addresses both molecular generation and property prediction tasks. However, the integration of these tasks is challenging due to inherent inconsistencies, making simple multi-task learning ineffective. To address this, we propose UniGEM, the first unified model to successfully integrate molecular generation and property prediction, delivering superior performance in both tasks. Our key innovation lies in a novel two-phase generative process, where predictive tasks are activated in the later stages, after the molecular scaffold is formed. We further enhance task balance through innovative training strategies. Rigorous theoretical analysis and comprehensive experiments demonstrate our significant improvements in both tasks. The principles behind UniGEM hold promise for broader applications, including natural language processing and computer vision.

ICML Conference 2024 Conference Paper

ESM All-Atom: Multi-Scale Protein Language Model for Unified Molecular Modeling

• Kangjie Zheng
• Siyu Long
• Tianyu Lu
• Junwei Yang
• Xinyu Dai
• Ming Zhang 0004
• Zaiqing Nie
• Wei-Ying Ma

Protein language models have demonstrated significant potential in the field of protein engineering. However, current protein language models primarily operate at the residue scale, which limits their ability to provide information at the atom level. This limitation prevents us from fully exploiting the capabilities of protein language models for applications involving both proteins and small molecules. In this paper, we propose ESM-AA (ESM All-Atom), a novel approach that enables atom-scale and residue-scale unified molecular modeling. ESM-AA achieves this by pre-training on multi-scale code-switch protein sequences and utilizing a multi-scale position encoding to capture relationships among residues and atoms. Experimental results indicate that ESM-AA surpasses previous methods in protein-molecule tasks, demonstrating the full utilization of protein language models. Further investigations reveal that through unified molecular modeling, ESM-AA not only gains molecular knowledge but also retains its understanding of proteins.

ICML Conference 2024 Conference Paper

Mol-AE: Auto-Encoder Based Molecular Representation Learning With 3D Cloze Test Objective

• Junwei Yang
• Kangjie Zheng
• Siyu Long
• Zaiqing Nie
• Ming Zhang 0004
• Xinyu Dai
• Wei-Ying Ma
• Hao Zhou 0012

3D molecular representation learning has gained tremendous interest and achieved promising performance in various downstream tasks. A series of recent approaches follow a prevalent framework: an encoder-only model coupled with a coordinate denoising objective. However, through a series of analytical experiments, we prove that the encoder-only model with coordinate denoising objective exhibits inconsistency between pre-training and downstream objectives, as well as issues with disrupted atomic identifiers. To address these two issues, we propose Mol-AE for molecular representation learning, an auto-encoder model using positional encoding as atomic identifiers. We also propose a new training objective named 3D Cloze Test to make the model learn better atom spatial relationships from real molecular substructures. Empirical results demonstrate that Mol-AE achieves a large margin performance gain compared to the current state-of-the-art 3D molecular modeling approach.

ICML Conference 2024 Conference Paper

MolCRAFT: Structure-Based Drug Design in Continuous Parameter Space

• Yanru Qu
• Keyue Qiu
• Yuxuan Song
• Jingjing Gong
• Jiawei Han 0001
• Mingyue Zheng
• Hao Zhou 0012
• Wei-Ying Ma

Generative models for structure-based drug design (SBDD) have shown promising results in recent years. Existing works mainly focus on how to generate molecules with higher binding affinity, ignoring the feasibility prerequisites for generated 3D poses and resulting in false positives. We conduct thorough studies on key factors of ill-conformational problems when applying autoregressive methods and diffusion to SBDD, including mode collapse and hybrid continuous-discrete space. In this paper, we introduce MolCRAFT, the first SBDD model that operates in the continuous parameter space, together with a novel noise reduced sampling strategy. Empirical results show that our model consistently achieves superior performance in binding affinity with more stable 3D structure, demonstrating our ability to accurately model interatomic interactions. To our best knowledge, MolCRAFT is the first to achieve reference-level Vina Scores (-6. 59 kcal/mol) with comparable molecular size, outperforming other strong baselines by a wide margin (-0. 84 kcal/mol). Code is available at https: //github. com/AlgoMole/MolCRAFT.

ICLR Conference 2024 Conference Paper

Protein-ligand binding representation learning from fine-grained interactions

• Shikun Feng
• Minghao Li
• Yinjun Jia
• Wei-Ying Ma
• Yanyan Lan

The binding between proteins and ligands plays a crucial role in the realm of drug discovery. Previous deep learning approaches have shown promising results over traditional computationally intensive methods, but resulting in poor generalization due to limited supervised data. In this paper, we propose to learn protein-ligand binding representation in a self-supervised learning manner. Different from existing pre-training approaches which treat proteins and ligands individually, we emphasize to discern the intricate binding patterns from fine-grained interactions. Specifically, this self-supervised learning problem is formulated as a prediction of the conclusive binding complex structure given a pocket and ligand with a Transformer based interaction module, which naturally emulates the binding process. To ensure the representation of rich binding information, we introduce two pre-training tasks, i.e. atomic pairwise distance map prediction and mask ligand reconstruction, which comprehensively model the fine-grained interactions from both structure and feature space. Extensive experiments have demonstrated the superiority of our method across various binding tasks, including protein-ligand affinity prediction, virtual screening and protein-ligand docking.

ICML Conference 2024 Conference Paper

Rethinking Specificity in SBDD: Leveraging Delta Score and Energy-Guided Diffusion

• Bowen Gao
• Minsi Ren
• Yuyan Ni
• Yanwen Huang
• Bo Qiang
• Zhiming Ma
• Wei-Ying Ma
• Yanyan Lan

In the field of Structure-based Drug Design (SBDD), deep learning-based generative models have achieved outstanding performance in terms of docking score. However, further study shows that the existing molecular generative methods and docking scores both have lacked consideration in terms of specificity, which means that generated molecules bind to almost every protein pocket with high affinity. To address this, we introduce the Delta Score, a new metric for evaluating the specificity of molecular binding. To further incorporate this insight for generation, we develop an innovative energy-guided approach using contrastive learning, with active compounds as decoys, to direct generative models toward creating molecules with high specificity. Our empirical results show that this method not only enhances the delta score but also maintains or improves traditional docking scores, successfully bridging the gap between SBDD and real-world needs.

ICLR Conference 2024 Conference Paper

Self-supervised Pocket Pretraining via Protein Fragment-Surroundings Alignment

• Bowen Gao
• Yinjun Jia
• Yuanle Mo
• Yuyan Ni
• Wei-Ying Ma
• Zhiming Ma
• Yanyan Lan

Pocket representations play a vital role in various biomedical applications, such as druggability estimation, ligand affinity prediction, and de novo drug design. While existing geometric features and pretrained representations have demonstrated promising results, they usually treat pockets independent of ligands, neglecting the fundamental interactions between them. However, the limited pocket-ligand complex structures available in the PDB database (less than 100 thousand non-redundant pairs) hampers large-scale pretraining endeavors for interaction modeling. To address this constraint, we propose a novel pocket pretraining approach that leverages knowledge from high-resolution atomic protein structures, assisted by highly effective pretrained small molecule representations. By segmenting protein structures into drug-like fragments and their corresponding pockets, we obtain a reasonable simulation of ligand-receptor interactions, resulting in the generation of over 5 million complexes. Subsequently, the pocket encoder is trained in a contrastive manner to align with the representation of pseudo-ligand furnished by some pretrained small molecule encoders. Our method, named ProFSA, achieves state-of-the-art performance across various tasks, including pocket druggability prediction, pocket matching, and ligand binding affinity prediction. Notably, ProFSA surpasses other pretraining methods by a substantial margin. Moreover, our work opens up a new avenue for mitigating the scarcity of protein-ligand complex data through the utilization of high-quality and diverse protein structure databases.

ICLR Conference 2024 Conference Paper

Sliced Denoising: A Physics-Informed Molecular Pre-Training Method

• Yuyan Ni
• Shikun Feng
• Wei-Ying Ma
• Zhiming Ma
• Yanyan Lan

While molecular pre-training has shown great potential in enhancing drug discovery, the lack of a solid physical interpretation in current methods raises concerns about whether the learned representation truly captures the underlying explanatory factors in observed data, ultimately resulting in limited generalization and robustness. Although denoising methods offer a physical interpretation, their accuracy is often compromised by ad-hoc noise design, leading to inaccurate learned force fields. To address this limitation, this paper proposes a new method for molecular pre-training, called sliced denoising (SliDe), which is based on the classical mechanical intramolecular potential theory. SliDe utilizes a novel noise strategy that perturbs bond lengths, angles, and torsion angles to achieve better sampling over conformations. Additionally, it introduces a random slicing approach that circumvents the computationally expensive calculation of the Jacobian matrix, which is otherwise essential for estimating the force field. By aligning with physical principles, SliDe shows a 42\% improvement in the accuracy of estimated force fields compared to current state-of-the-art denoising methods, and thus outperforms traditional baselines on various molecular property prediction tasks.

ICML Conference 2024 Conference Paper

UniCorn: A Unified Contrastive Learning Approach for Multi-view Molecular Representation Learning

• Shikun Feng
• Yuyan Ni
• Minghao Li
• Yanwen Huang
• Zhiming Ma
• Wei-Ying Ma
• Yanyan Lan

Recently, a noticeable trend has emerged in developing pre-trained foundation models in the domains of CV and NLP. However, for molecular pre-training, there lacks a universal model capable of effectively applying to various categories of molecular tasks, since existing prevalent pre-training methods exhibit effectiveness for specific types of downstream tasks. Furthermore, the lack of profound understanding of existing pre-training methods, including 2D graph masking, 2D-3D contrastive learning, and 3D denoising, hampers the advancement of molecular foundation models. In this work, we provide a unified comprehension of existing pre-training methods through the lens of contrastive learning. Thus their distinctions lie in clustering different views of molecules, which is shown beneficial to specific downstream tasks. To achieve a complete and general-purpose molecular representation, we propose a novel pre-training framework, named UniCorn, that inherits the merits of the three methods, depicting molecular views in three different levels. SOTA performance across quantum, physicochemical, and biological tasks, along with comprehensive ablation study, validate the universality and effectiveness of UniCorn.

ICLR Conference 2024 Conference Paper

Unified Generative Modeling of 3D Molecules with Bayesian Flow Networks

• Yuxuan Song
• Jingjing Gong
• Hao Zhou 0012
• Mingyue Zheng
• Jingjing Liu
• Wei-Ying Ma

Advanced generative model (\textit{e.g.}, diffusion model) derived from simplified continuity assumptions of data distribution, though showing promising progress, has been difficult to apply directly to geometry generation applications due to the \textit{multi-modality} and \textit{noise-sensitive} nature of molecule geometry. This work introduces Geometric Bayesian Flow Networks (GeoBFN), which naturally fits molecule geometry by modeling diverse modalities in the differentiable parameter space of distributions. GeoBFN maintains the SE-(3) invariant density modeling property by incorporating equivariant inter-dependency modeling on parameters of distributions and unifying the probabilistic modeling of different modalities. Through optimized training and sampling techniques, we demonstrate that GeoBFN achieves state-of-the-art performance on multiple 3D molecule generation benchmarks in terms of generation quality (90.87\% molecule stability in QM9 and 85.6\% atom stability in GEOM-DRUG\footnote{The scores are reported at 1k sampling steps for fair comparison, and our scores could be further improved if sampling sufficiently longer steps.}). GeoBFN can also conduct sampling with any number of steps to reach an optimal trade-off between efficiency and quality (\textit{e.g.}, 20$\times$ speedup without sacrificing performance).

ICML Conference 2023 Conference Paper

Coarse-to-Fine: a Hierarchical Diffusion Model for Molecule Generation in 3D

• Bo Qiang
• Yuxuan Song
• Minkai Xu
• Jingjing Gong
• Bowen Gao
• Hao Zhou 0012
• Wei-Ying Ma
• Yanyan Lan

Generating desirable molecular structures in 3D is a fundamental problem for drug discovery. Despite the considerable progress we have achieved, existing methods usually generate molecules in atom resolution and ignore intrinsic local structures such as rings, which leads to poor quality in generated structures, especially when generating large molecules. Fragment-based molecule generation is a promising strategy, however, it is nontrivial to be adapted for 3D non-autoregressive generations because of the combinational optimization problems. In this paper, we utilize a coarse-to-fine strategy to tackle this problem, in which a Hierarchical Diffusion-based model (i. e. HierDiff) is proposed to preserve the validity of local segments without relying on autoregressive modeling. Specifically, HierDiff first generates coarse-grained molecule geometries via an equivariant diffusion process, where each coarse-grained node reflects a fragment in a molecule. Then the coarse-grained nodes are decoded into fine-grained fragments by a message-passing process and a newly designed iterative refined sampling module. Lastly, the fine-grained fragments are then assembled to derive a complete atomic molecular structure. Extensive experiments demonstrate that HierDiff consistently improves the quality of molecule generation over existing methods.

NeurIPS Conference 2023 Conference Paper

DrugCLIP: Contrastive Protein-Molecule Representation Learning for Virtual Screening

• Bowen Gao
• Bo Qiang
• Haichuan Tan
• Yinjun Jia
• Minsi Ren
• Minsi Lu
• Jingjing Liu
• Wei-Ying Ma

Virtual screening, which identifies potential drugs from vast compound databases to bind with a particular protein pocket, is a critical step in AI-assisted drug discovery. Traditional docking methods are highly time-consuming, and can only work with a restricted search library in real-life applications. Recent supervised learning approaches using scoring functions for binding-affinity prediction, although promising, have not yet surpassed docking methods due to their strong dependency on limited data with reliable binding-affinity labels. In this paper, we propose a novel contrastive learning framework, DrugCLIP, by reformulating virtual screening as a dense retrieval task and employing contrastive learning to align representations of binding protein pockets and molecules from a large quantity of pairwise data without explicit binding-affinity scores. We also introduce a biological-knowledge inspired data augmentation strategy to learn better protein-molecule representations. Extensive experiments show that DrugCLIP significantly outperforms traditional docking and supervised learning methods on diverse virtual screening benchmarks with highly reduced computation time, especially in zero-shot setting.

NeurIPS Conference 2023 Conference Paper

Equivariant Flow Matching with Hybrid Probability Transport for 3D Molecule Generation

• Yuxuan Song
• Jingjing Gong
• Minkai Xu
• Ziyao Cao
• Yanyan Lan
• Stefano Ermon
• Hao Zhou
• Wei-Ying Ma

The generation of 3D molecules requires simultaneously deciding the categorical features (atom types) and continuous features (atom coordinates). Deep generative models, especially Diffusion Models (DMs), have demonstrated effectiveness in generating feature-rich geometries. However, existing DMs typically suffer from unstable probability dynamics with inefficient sampling speed. In this paper, we introduce geometric flow matching, which enjoys the advantages of both equivariant modeling and stabilized probability dynamics. More specifically, we propose a hybrid probability path where the coordinates probability path is regularized by an equivariant optimal transport, and the information between different modalities is aligned. Experimentally, the proposed method could consistently achieve better performance on multiple molecule generation benchmarks with 4. 75$\times$ speed up of sampling on average.

ICML Conference 2023 Conference Paper

Fractional Denoising for 3D Molecular Pre-training

• Shikun Feng
• Yuyan Ni
• Yanyan Lan
• Zhiming Ma
• Wei-Ying Ma

Coordinate denoising is a promising 3D molecular pre-training method, which has achieved remarkable performance in various downstream drug discovery tasks. Theoretically, the objective is equivalent to learning the force field, which is revealed helpful for downstream tasks. Nevertheless, there are two challenges for coordinate denoising to learn an effective force field, i. e. low coverage samples and isotropic force field. The underlying reason is that molecular distributions assumed by existing denoising methods fail to capture the anisotropic characteristic of molecules. To tackle these challenges, we propose a novel hybrid noise strategy, including noises on both dihedral angel and coordinate. However, denoising such hybrid noise in a traditional way is no more equivalent to learning the force field. Through theoretical deductions, we find that the problem is caused by the dependency of the input conformation for covariance. To this end, we propose to decouple the two types of noise and design a novel fractional denoising method (Frad), which only denoises the latter coordinate part. In this way, Frad enjoys both the merits of sampling more low-energy structures and the force field equivalence. Extensive experiments show the effectiveness of Frad in molecule representation, with a new state-of-the-art on 9 out of 12 tasks of QM9 and on 7 out of 8 targets of MD17.

ICLR Conference 2022 Conference Paper

Energy-Inspired Molecular Conformation Optimization

• Jiaqi Guan
• Wesley Wei Qian
• Qiang Liu 0001
• Wei-Ying Ma
• Jianzhu Ma
• Jian Peng 0001

This paper studies an important problem in computational chemistry: predicting a molecule's spatial atom arrangements, or a molecular conformation. We propose a neural energy minimization formulation that casts the prediction problem into an unrolled optimization process, where a neural network is parametrized to learn the gradient fields of an implicit conformational energy landscape. Assuming different forms of the underlying potential energy function, we can not only reinterpret and unify many of the existing models but also derive new variants of SE(3)-equivariant neural networks in a principled manner. In our experiments, these new variants show superior performance in molecular conformation optimization comparing to existing SE(3)-equivariant neural networks. Moreover, our energy-inspired formulation is also suitable for molecular conformation generation, where we can generate more diverse and accurate conformers comparing to existing baselines.

AAAI Conference 2017 Conference Paper

Topic Aware Neural Response Generation

• Chen Xing
• Wei Wu
• Yu Wu
• Jie Liu
• Yalou Huang
• Ming Zhou
• Wei-Ying Ma

We consider incorporating topic information into a sequenceto-sequence framework to generate informative and interesting responses for chatbots. To this end, we propose a topic aware sequence-to-sequence (TA-Seq2Seq) model. The model utilizes topics to simulate prior human knowledge that guides them to form informative and interesting responses in conversation, and leverages topic information in generation by a joint attention mechanism and a biased generation probability. The joint attention mechanism summarizes the hidden vectors of an input message as context vectors by message attention and synthesizes topic vectors by topic attention from the topic words of the message obtained from a pre-trained LDA model, with these vectors jointly affecting the generation of words in decoding. To increase the possibility of topic words appearing in responses, the model modifies the generation probability of topic words by adding an extra probability item to bias the overall distribution. Empirical studies on both automatic evaluation metrics and human annotations show that TA-Seq2Seq can generate more informative and interesting responses, significantly outperforming state-of-theart response generation models.

NeurIPS Conference 2016 Conference Paper

Dual Learning for Machine Translation

• Di He
• Yingce Xia
• Tao Qin
• Liwei Wang
• Nenghai Yu
• Tie-Yan Liu
• Wei-Ying Ma

While neural machine translation (NMT) is making good progress in the past two years, tens of millions of bilingual sentence pairs are needed for its training. However, human labeling is very costly. To tackle this training data bottleneck, we develop a dual-learning mechanism, which can enable an NMT system to automatically learn from unlabeled data through a dual-learning game. This mechanism is inspired by the following observation: any machine translation task has a dual task, e. g. , English-to-French translation (primal) versus French-to-English translation (dual); the primal and dual tasks can form a closed loop, and generate informative feedback signals to train the translation models, even if without the involvement of a human labeler. In the dual-learning mechanism, we use one agent to represent the model for the primal task and the other agent to represent the model for the dual task, then ask them to teach each other through a reinforcement learning process. Based on the feedback signals generated during this process (e. g. , the language-model likelihood of the output of a model, and the reconstruction error of the original sentence after the primal and dual translations), we can iteratively update the two models until convergence (e. g. , using the policy gradient methods). We call the corresponding approach to neural machine translation \emph{dual-NMT}. Experiments show that dual-NMT works very well on English$\leftrightarrow$French translation; especially, by learning from monolingual data (with 10\% bilingual data for warm start), it achieves a comparable accuracy to NMT trained from the full bilingual data for the French-to-English translation task.

AAAI Conference 2016 Conference Paper

Hashtag-Based Sub-Event Discovery Using Mutually Generative LDA in Twitter

• Chen Xing
• Yuan Wang
• Jie Liu
• Yalou Huang
• Wei-Ying Ma

Sub-event discovery is an effective method for social event analysis in Twitter. It can discover sub-events from large amount of noisy event-related information in Twitter and semantically represent them. The task is challenging because tweets are short, informal and noisy. To solve this problem, we consider leveraging event-related hashtags that contain many locations, dates and concise sub-event related descriptions to enhance sub-event discovery. To this end, we propose a hashtag-based mutually generative Latent Dirichlet Allocation model(MGe-LDA). In MGe-LDA, hashtags and topics of a tweet are mutually generated by each other. The mutually generative process models the relationship between hashtags and topics of tweets, and highlights the role of hashtags as a semantic representation of the corresponding tweets. Experimental results show that MGe-LDA can significantly outperform state-of-the-art methods for sub-event discovery.

ICML Conference 2005 Conference Paper

2D Conditional Random Fields for Web information extraction

• Jun Zhu 0001
• Zaiqing Nie
• Ji-Rong Wen
• Bo Zhang 0010
• Wei-Ying Ma

ICML Conference 2003 Conference Paper

An Evaluation on Feature Selection for Text Clustering

• Tao Liu
• Shengping Liu
• Zheng Chen 0001
• Wei-Ying Ma

UAI Conference 2003 Conference Paper

Collaborative Ensemble Learning: Combining Collaborative and Content-Based Information Filtering via Hierarchical Bayes

• Kai Yu 0001
• Anton Schwaighofer
• Volker Tresp
• Wei-Ying Ma
• HongJiang Zhang

Collaborative filtering (CF) and content-based filtering (CBF) have widely been used in information filtering applications. Both approaches have their strengths and weaknesses which is why researchers have developed hybrid systems. This paper proposes a novel approach to unify CF and CBF in a probabilistic framework, named collaborative ensemble learning. It uses probabilistic SVMs to model each user's profile (as CBF does).At the prediction phase, it combines a society OF users profiles, represented by their respective SVM models, to predict an active users preferences(the CF idea ).The combination scheme is embedded in a probabilistic framework and retains an intuitive explanation.Moreover, collaborative ensemble learning does not require a global training stage and thus can incrementally incorporate new data.We report results based on two data sets. For the Reuters-21578 text data set, we simulate user ratings under the assumption that each user is interested in only one category. In the second experiment, we use users' opinions on a set of 642 art images that were collected through a web-based survey. For both data sets, collaborative ensemble achieved excellent performance in terms of recommendation accuracy.