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Stan Z. Li

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79 papers
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79

AAAI Conference 2026 Conference Paper

Departures: Distributional Transport for Single-Cell Perturbation Prediction with Neural Schrödinger Bridges

  • Changxi Chi
  • Yufei Huang
  • Jun Xia
  • Jiangbin Zheng
  • Yunfan Liu
  • Zelin Zang
  • Stan Z. Li

Predicting single-cell perturbation outcomes directly advances gene function analysis and facilitates drug candidate selection, making it a key driver of both basic and translational biomedical research. However, a major bottleneck in this task is the unpaired nature of single-cell data, as the same cell cannot be observed both before and after perturbation due to the destructive nature of sequencing. Although some neural generative transport models attempt to tackle unpaired single-cell perturbation data, they either lack explicit conditioning or depend on prior spaces for indirect distribution alignment, limiting precise perturbation modeling. In this work, we approximate Schrödinger Bridge (SB), which defines stochastic dynamic mappings recovering the entropy-regularized optimal transport (OT), to directly align the distributions of control and perturbed single-cell populations across different perturbation conditions. Unlike prior SB approximations that rely on bidirectional modeling to infer optimal source-target sample coupling, we leverage Minibatch-OT based pairing to avoid such bidirectional inference and the associated ill-posedness of defining the reverse process. This pairing directly guides bridge learning, yielding a scalable approximation to the SB. We approximate two SB models, one modeling discrete gene activation states and the other continuous expression distributions. Joint training enables accurate perturbation modeling and captures single-cell heterogeneity. Experiments on public genetic and drug perturbation datasets show that our model effectively captures heterogeneous single-cell responses and achieves state-of-the-art performance.

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AAAI Conference 2026 Conference Paper

Learning Cell-Aware Hierarchical Multi-Modal Representations for Robust Molecular Modeling

  • Mengran Li
  • Zelin Zang
  • Wenbin Xing
  • Junzhou Chen
  • Ronghui Zhang
  • Jiebo Luo
  • Stan Z. Li

Understanding how chemical perturbations propagate through biological systems is essential for robust molecular property prediction. While most existing methods focus on chemical structures alone, recent advances highlight the crucial role of cellular responses such as morphology and gene expression in shaping drug effects. However, current cell-aware approaches face two key limitations: (1) modality incompleteness in external biological data, and (2) insufficient modeling of hierarchical dependencies across molecular, cellular, and genomic levels. We propose CHMR (Cell-aware Hierarchical Multi-Modal Representations), a robust framework that jointly models local-global dependencies between molecules and cellular responses and captures latent biological hierarchies via a novel tree-structured vector quantization module. Evaluated on public benchmarks spanning 696 tasks, CHMR outperforms state-of-the-art baselines, yielding average improvements of 3.6% on classification and 17.2% on regression tasks. These results demonstrate the advantage of hierarchy-aware, multi-modal learning for reliable and biologically grounded molecular representations, offering a generalizable framework for integrative biomedical modeling.

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AAAI Conference 2026 Conference Paper

MergeDNA: Context-Aware Genome Modeling with Dynamic Tokenization Through Token Merging

  • Siyuan Li
  • Kai Yu
  • Anna Wang
  • Zicheng Liu
  • Chang Yu
  • Jingbo Zhou
  • Qirong Yang
  • Yucheng Guo

Modeling genomic sequences faces two unsolved challenges: the information density varies widely across different regions, while there is no clearly defined minimum vocabulary unit. Relying on either four primitive bases or independently designed DNA tokenizers, existing approaches with naive masked language modeling pre-training often fail to adapt to the varying complexities of genomic sequences. Leveraging Token Merging techniques, this paper introduces a hierarchical architecture that jointly optimizes a dynamic genomic tokenizer and latent Transformers with context-aware pre-training tasks. As for network structures, the tokenization module automatically chunks adjacent bases into words by stacking multiple layers of the differentiable token merging blocks with local-window constraints, then a Latent Encoder captures the global context of these merged words by full-attention blocks. Symmetrically employing a Latent Decoder and a Local Decoder, MergeDNA learns with two pre-training tasks: Merged Token Reconstruction simultaneously trains the dynamic tokenization module and adaptively filters important tokens, while Adaptive Masked Token Modeling learns to predict these filtered tokens to capture informative contents. Extensive experiments show that MergeDNA achieves superior performance on three popular DNA benchmarks and several multi-omics tasks with fine-tuning or zero-shot evaluation, outperforming typical tokenization methods and large-scale DNA foundation models.

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IJCAI Conference 2025 Conference Paper

A Comprehensive and Systematic Review for Deep Learning-Based De Novo Peptide Sequencing

  • Jun Xia
  • Jingbo Zhou
  • Shaorong Chen
  • Tianze Ling
  • Stan Z. Li

Tandem mass spectrometry (MS/MS) has revolutionized the field of proteomics, enabling the high-throughput identification of proteins. However, one of the central challenges in mass spectrometry-based proteomics remains peptide identification, especially in the absence of a comprehensive peptide database. While traditional database search methods compare observed mass spectra to pre-existing protein databases, they are limited by the availability and completeness of these databases. \emph{De novo} peptide sequencing, which derives peptide sequences directly from mass spectra, has emerged as a crucial approach in such cases. In recent years, deep learning has made significant strides in this domain. These methods train deep neural networks for translating mass spectra into peptide sequences without relying on any pre-constructed databases. Despite significant progress, this field still lacks a comprehensive and systematic review. In this paper, we provide the first review of deep learning-based \emph{de novo} peptide sequencing techniques from the perspectives of data types, model architectures, decoding strategies, applications and evaluation metrics. We also identify key challenges and highlight promising avenues for future research, providing a valuable resource for the AI and scientific communities.

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ICLR Conference 2025 Conference Paper

A Simple yet Effective ΔΔG Predictor is An Unsupervised Antibody Optimizer and Explainer

  • Lirong Wu
  • Yunfan Liu 0002
  • Haitao Lin
  • Yufei Huang 0002
  • Guojiang Zhao
  • Zhifeng Gao
  • Stan Z. Li

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 ($\Delta\Delta G$) 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 $\Delta\Delta G$ 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 $\Delta\Delta G$ predictor (Light-DDG), which adopts a structure-aware Transformer as the backbone and enhances it by knowledge distilled from existing powerful but computationally heavy $\Delta\Delta G$ 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. Extensive experiments have demonstrated the effectiveness of Light-DDG in terms of test generalizability, noise robustness, and inference practicality, e.g., 89.7$\times$ inference acceleration and 15.45\% performance gains over previous state-of-the-art baselines. A case study of SARS-CoV-2 further demonstrates the crucial role of Light-DDG for mutation explanation and antibody optimization.

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NeurIPS Conference 2025 Conference Paper

AlphaFold Database Debiasing for Robust Inverse Folding

  • Cheng Tan
  • Zhenxiao Cao
  • Zhangyang Gao
  • Siyuan Li
  • Yufei Huang
  • Stan Z. Li

The AlphaFold Protein Structure Database (AFDB) offers unparalleled structural coverage at near-experimental accuracy, positioning it as a valuable resource for data-driven protein design. However, its direct use in training deep models that are sensitive to fine-grained atomic geometry—such as inverse folding—exposes a critical limitation. Comparative analysis of structural feature distributions reveals that AFDB structures exhibit distinct statistical regularities, reflecting a systematic geometric bias that deviates from the conformational diversity found in experimentally determined structures from the Protein Data Bank (PDB). While AFDB structures are cleaner and more idealized, PDB structures capture the intrinsic variability and physical realism essential for generalization in downstream tasks. To address this discrepancy, we introduce a Debiasing Structure AutoEncoder (DeSAE) that learns to reconstruct native-like conformations from intentionally corrupted backbone geometries. By training the model to recover plausible structural states, DeSAE implicitly captures a more robust and natural structural manifold. At inference, applying DeSAE to AFDB structures produces debiased structures that significantly improve inverse folding performance across multiple benchmarks. This work highlights the critical impact of subtle systematic biases in predicted structures and presents a principled framework for debiasing, significantly boosting the performance of structure-based learning tasks like inverse folding.

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ICLR Conference 2025 Conference Paper

Bridging the Gap between Database Search and De Novo Peptide Sequencing with SearchNovo

  • Jun Xia 0001
  • Sizhe Liu
  • Jingbo Zhou
  • Shaorong Chen
  • Hongxin Xiang
  • Zicheng Liu 0006
  • Yue Liu 0008
  • Stan Z. Li

Accurate protein identification from mass spectrometry (MS) data is fundamental to unraveling the complex roles of proteins in biological systems, with peptide sequencing being a pivotal step in this process. The two main paradigms for peptide sequencing are database search, which matches experimental spectra with peptide sequences from databases, and \emph{de novo} sequencing, which infers peptide sequences directly from MS without relying on pre-constructed database. Although database search methods are highly accurate, they are limited by their inability to identify novel, modified, or mutated peptides absent from the database. In contrast, \emph{de novo} sequencing is adept at discovering novel peptides but often struggles with missing peaks issue, further leading to lower precision. We introduce SearchNovo, a novel framework that synergistically integrates the strengths of database search and \emph{de novo} sequencing to enhance peptide sequencing. SearchNovo employs an efficient search mechanism to retrieve the most similar peptide spectrum match (PSM) from a database for each query spectrum, followed by a fusion module that utilizes the reference peptide sequence to guide the generation of the target sequence. Furthermore, we observed that dissimilar (noisy) reference peptides negatively affect model performance. To mitigate this, we constructed pseudo reference PSMs to minimize their impact. Comprehensive evaluations on multiple datasets reveal that SearchNovo significantly outperforms state-of-the-art models. Also, analysis indicates that many retrieved spectra contain missing peaks absent in the query spectra, and the retrieved reference peptides often share common fragments with the target peptides. These are key elements in the recipe for SearchNovo’s success. The code is available at: \textcolor{magenta}{\url{https://github.com/junxia97/SearchNovo}}.

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ICLR Conference 2025 Conference Paper

CBGBench: Fill in the Blank of Protein-Molecule Complex Binding Graph

  • Haitao Lin
  • Guojiang Zhao
  • Odin Zhang
  • Yufei Huang 0002
  • Lirong Wu
  • Cheng Tan 0012
  • Zicheng Liu 0006
  • Zhifeng Gao

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 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 cutting-edge methods. Secondly, a single de novo molecule generation task can hardly reflect their capabilities. To broaden the scope, we adapt these models to a range of tasks essential in drug design, considered sub-tasks within the graph fill-in-the-blank tasks. These tasks include the generative designation of 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 insights with analysis from empirical studies. Our results indicate that there is potential for further improvements on many tasks, with optimization in network architectures, and effective incorporation of chemical prior knowledge. Finally, to lower the barrier to entry and facilitate further developments in the field, we also provide a single [codebase](https://github.com/EDAPINENUT/CBGBench) that unifies the discussed models, data pre-processing, training, sampling, and evaluation.

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AAAI Conference 2025 Conference Paper

dyAb: Flow Matching for Flexible Antibody Design with AlphaFold-driven Pre-binding Antigen

  • Cheng Tan
  • Yijie Zhang
  • Zhangyang Gao
  • Yufei Huang
  • Haitao Lin
  • Lirong Wu
  • Fandi Wu
  • Mathieu Blanchette

The development of therapeutic antibodies heavily relies on accurate predictions of how antigens will interact with antibodies. Existing computational methods in antibody design often overlook crucial conformational changes that antigens undergo during the binding process, significantly impacting the reliability of the resulting antibodies. To bridge this gap, we introduce dyAb, a flexible framework that incorporates AlphaFold2-driven predictions to model pre-binding antigen structures and specifically addresses the dynamic nature of antigen conformation changes. Our dyAb model leverages a unique combination of coarse-grained interface alignment and fine-grained flow matching techniques to simulate the interaction dynamics and structural evolution of the antigen-antibody complex, providing a realistic representation of the binding process. Extensive experiments show that dyAb significantly outperforms existing models in antibody design involving changing antigen conformations. These results highlight dyAb's potential to streamline the design process for therapeutic antibodies, promising more efficient development cycles and improved outcomes in clinical applications.

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TMLR Journal 2025 Journal Article

Dynamics-inspired Structure Hallucination for Protein-protein Interaction Modeling

  • Fang Wu
  • Stan Z. Li

Protein-protein interaction (PPI) represents a central challenge within the biology field, and accurately predicting the consequences of mutations in this context is crucial for drug design and protein engineering. Deep learning (DL) has shown promise in forecasting the effects of such mutations but is hindered by two primary constraints. First, the structures of mutant proteins are often elusive to acquire. Secondly, PPI takes place dynamically, which is rarely integrated into the DL architecture design. To address these obstacles, we present a novel framework named Refine-PPI with two key enhancements. First, we introduce a structure refinement module trained by a mask mutation modeling (MMM) task on available wild-type structures, which is then transferred to hallucinate the inaccessible mutant structures. Second, we employ a new kind of geometric network, called the probability density cloud network (PDC-Net), to capture 3D dynamic variations and encode the atomic uncertainty associated with PPI. Comprehensive experiments on SKEMPI.v2 substantiate the superiority of Refine-PPI over all existing tools for predicting free energy change. These findings underscore the effectiveness of our hallucination strategy and the PDC module in addressing the absence of mutant protein structure and modeling geometric uncertainty.

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ICLR Conference 2025 Conference Paper

EVA: Geometric Inverse Design for Fast Protein Motif-Scaffolding with Coupled Flow

  • Yufei Huang 0002
  • Yunshu Liu
  • Lirong Wu
  • Haitao Lin
  • Cheng Tan 0012
  • Odin Zhang
  • Zhangyang Gao
  • Siyuan Li 0002

Motif-scaffolding is a fundamental component of protein design, which aims to construct the scaffold structure that stabilizes motifs conferring desired functions. Recent advances in generative models are promising for designing scaffolds, with two main approaches: training-based and sampling-based methods. Training-based methods are resource-heavy and slow, while training-free sampling-based methods are flexible but require numerous sampling steps and costly, unstable guidance. To speed up and improve sampling-based methods, we analyzed failure cases and found that errors stem from the trade-off between generation and guidance. Thus we proposed to exploit the spatial context and adjust the generative direction to be consistent with guidance to overcome this trade-off. Motivated by this, we formulate motif-scaffolding as a Geometric Inverse Design task inspired by the image inverse problem, and present Evolution-ViA-reconstruction (EVA), a novel sampling-based coupled flow framework on geometric manifolds, which starts with a pretrained flow-based generative model. EVA uses motif-coupled priors to leverage spatial contexts, guiding the generative process along a straighter probability path, with generative directions aligned with guidance in the early sampling steps. EVA is 70× faster than SOTA model RFDiffusion with competitive and even better performance on benchmark tests. Further experiments on real-world cases including vaccine design, multi-motif scaffolding and motif optimal placement searching demonstrate EVA's superior efficiency and effectiveness.

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AAAI Conference 2025 Conference Paper

FoldToken: Learning Protein Language via Vector Quantization and Beyond

  • Zhangyang Gao
  • Cheng Tan
  • Jue Wang
  • Yufei Huang
  • Lirong Wu
  • Stan Z. Li

Is there a foreign language describing protein sequences and structures simultaneously? Protein structures, represented by continuous 3D points, have long posed a challenge due to the contrasting modeling paradigms of discrete sequences. We introduce FoldTokenizer to represent protein sequence-structure as discrete symbols. This approach involves projecting residue types and structures into a discrete space, guided by a reconstruction loss for information preservation. We name the learned discrete symbols as FoldToken, and the sequence of FoldTokens serves as a new protein language, transforming the protein sequence-structure into a unified modality. We apply the created protein language on general backbone inpainting task, building the first GPT-style model (FoldGPT) for sequence-structure co-generation with promising results. Key to our success is the substantial enhancement of the vector quantization module, Soft Conditional Vector Quantization (SoftCVQ).

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AAAI Conference 2025 Conference Paper

Generalized Implicit Neural Representations for Dynamic Molecular Surface Modeling

  • Fang Wu
  • Bozhen Hu
  • Stan Z. Li

Molecular dynamics (MD) has long been the de facto choice for simulating intricate physical systems from first principles. Recent efforts utilize the implicit neural representation (INR) to directly learn surface point clouds' signed distance function (SDF) with promising outcomes. However, INR's temporal generalization to unexplored molecular systems remains limited, which poses a significant barrier to applying INR to a broader range of real-world scenarios. This study introduces MoE-DSR, an enhanced version of dynamic surface representations (DSR) that effectively integrates the mixture-of-experts (MoE) strategy. Specifically, the router employs a novel geometric surface cloud network to extract the structural information from the initial static protein conformation as the prior knowledge. Meanwhile, experts compromising a team of equivariant implicit neural networks (E-INNs), each responsible for distinct protein families, ensure precise SDF estimation across varied protein data landscapes. We showcase the ability of MoE-DSR to model dynamic protein surface shapes using ensembles from ATLAS, the largest available protein MD simulations database. Extensive experiments validate its effectiveness in analyzing complex molecular systems across continuous space and time domains.

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IJCAI Conference 2025 Conference Paper

GRAPE: Heterogeneous Graph Representation Learning for Genetic Perturbation with Coding and Non-Coding Biotype

  • Changxi Chi
  • Jun Xia
  • Jingbo Zhou
  • Jiabei Cheng
  • Chang Yu
  • Stan Z. Li

Predicting genetic perturbations enables the identification of potentially crucial genes prior to wet-lab experiments, significantly improving overall experimental efficiency. Since genes are the foundation of cellular life, building gene regulatory networks (GRN) is essential to understand and predict the effects of genetic perturbations. However, current methods fail to fully leverage gene-related information, and solely rely on simple evaluation metrics to construct coarse-grained GRN. More importantly, they ignore functional differences between biotypes, limiting the ability to capture potential gene interactions. In this work, we leverage pre-trained large language model and DNA sequence model to extract features from gene descriptions and DNA sequence data, respectively, which serve as the initialization for gene representations. Additionally, we introduce gene biotype information for the first time in genetic perturbation, simulating the distinct roles of genes with different biotypes in regulating cellular processes, while capturing implicit gene relationships through graph structure learning (GSL). We propose GRAPE, a heterogeneous graph neural network (HGNN) that leverages gene representations initialized with features from descriptions and sequences, models the distinct roles of genes with different biotypes, and dynamically refines the GRN through GSL. The results on publicly available datasets show that our method achieves state-of-the-art performance. The code for reproducing the results can be seen at the link: https: //github. com/ChangxiChi/GRAPE.

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TMLR Journal 2025 Journal Article

MDTree: A Masked Dynamic Autoregressive Model for Phylogenetic Inference

  • Zelin Zang
  • ChenRui Duan
  • Siyuan Li
  • Jinlin Wu
  • BingoWing-Kuen Ling
  • Fuji Yang
  • Jiebo Luo
  • Zhen Lei

Phylogenetic tree inference requires optimizing both branch lengths and topologies, yet traditional MCMC-based methods suffer from slow convergence and high computational cost. Recent deep learning approaches improve scalability but remain constrained: Bayesian models are computationally intensive, autoregressive methods depend on fixed species orders, and flow-based models underutilize genomic signals. Fixed-order autoregression introduces an inductive bias misaligned with evolutionary proximity: early misplacements distort subsequent attachment probabilities and compound topology errors (exposure bias). Absent sequence-informed priors, the posterior over the super-exponential topology space remains diffuse and multimodal, yielding high-variance gradients and sluggish convergence for both MCMC proposals and neural samplers. We propose MDTree, a masked dynamic autoregressive framework that integrates genomic priors into a Dynamic Ordering Network to learn biologically informed node sequences. A dynamic masking mechanism further enables parallel node insertion, improving efficiency without sacrificing accuracy. Experiments on standard benchmarks demonstrate that MDTree outperforms existing methods in accuracy and runtime while producing biologically coherent phylogenies, providing a scalable solution for large-scale evolutionary analysis.

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ICLR Conference 2025 Conference Paper

MeToken: Uniform Micro-environment Token Boosts Post-Translational Modification Prediction

  • Cheng Tan 0012
  • Zhenxiao Cao
  • Zhangyang Gao
  • Lirong Wu
  • Siyuan Li 0002
  • Yufei Huang 0002
  • Jun Xia 0001
  • Bozhen Hu

Post-translational modifications (PTMs) profoundly expand the complexity and functionality of the proteome, regulating protein attributes and interactions that are crucial for biological processes. Accurately predicting PTM sites and their specific types is therefore essential for elucidating protein function and understanding disease mechanisms. Existing computational approaches predominantly focus on protein sequences to predict PTM sites, driven by the recognition of sequence-dependent motifs. However, these approaches often overlook protein structural contexts. In this work, we first compile a large-scale sequence-structure PTM dataset, which serves as the foundation for fair comparison. We introduce the MeToken model, which tokenizes the micro-environment of each amino acid, integrating both sequence and structural information into unified discrete tokens. This model not only captures the typical sequence motifs associated with PTMs but also leverages the spatial arrangements dictated by protein tertiary structures, thus providing a holistic view of the factors influencing PTM sites. Designed to address the long-tail distribution of PTM types, MeToken employs uniform sub-codebooks that ensure even the rarest PTMs are adequately represented and distinguished. We validate the effectiveness and generalizability of MeToken across multiple datasets, demonstrating its superior performance in accurately identifying PTM types. The results underscore the importance of incorporating structural data and highlight MeToken's potential in facilitating accurate and comprehensive PTM predictions, which could significantly impact proteomics research.

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NeurIPS Conference 2025 Conference Paper

PRING: Rethinking Protein-Protein Interaction Prediction from Pairs to Graphs

  • Xinzhe Zheng
  • Hao Du
  • Fanding Xu
  • Jinzhe Li
  • Zhiyuan Liu
  • Wenkang Wang
  • Tao Chen
  • Wanli Ouyang

Deep learning-based computational methods have achieved promising results in predicting protein-protein interactions (PPIs). However, existing benchmarks predominantly focus on isolated pairwise evaluations, overlooking a model's capability to reconstruct biologically meaningful PPI networks, which is crucial for biology research. To address this gap, we introduce PRING, the first comprehensive benchmark that evaluates PRotein-protein INteraction prediction from a Graph-level perspective. PRING curates a high-quality, multi-species PPI network dataset comprising 21, 484 proteins and 186, 818 interactions, with well-designed strategies to address both data redundancy and leakage. Building on this golden-standard dataset, we establish two complementary evaluation paradigms: (1) topology-oriented tasks, which assess intra and cross-species PPI network construction, and (2) function-oriented tasks, including protein complex pathway prediction, GO module analysis, and essential protein justification. These evaluations not only reflect the model's capability to understand the network topology but also facilitate protein function annotation, biological module detection, and even disease mechanism analysis. Extensive experiments on four representative model categories, consisting of sequence similarity-based, naive sequence-based, protein language model-based, and structure-based approaches, demonstrate that current PPI models have potential limitations in recovering both structural and functional properties of PPI networks, highlighting the gap in supporting real-world biological applications. We believe PRING provides a reliable platform to guide the development of more effective PPI prediction models for the community. The dataset and source code of PRING are available at https: //github. com/SophieSarceau/PRING.

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AAAI Conference 2025 Conference Paper

Relation-Aware Equivariant Graph Networks for Epitope-Unknown Antibody Design and Specificity Optimization

  • Lirong Wu
  • Haitao Lin
  • Yufei Huang
  • Zhangyang Gao
  • Cheng Tan
  • Yunfan Liu
  • Tailin Wu
  • Stan Z. Li

Antibodies are Y-shaped proteins that protect the host by binding to specific antigens, and their binding is mainly determined by the Complementary Determining Regions (CDRs) in the antibody. Despite the great progress made in CDR design, existing computational methods still encounter several challenges: 1) poor capability of modeling complex CDRs with long sequences due to insufficient contextual information; 2) conditioned on pre-given antigenic epitopes and their static interaction with the target antibody; 3) neglect of specificity during antibody optimization leads to non-specific antibodies. In this paper, we take into account a variety of node features, edge features, and edge relations to include more contextual and geometric information. We propose a novel Relation-Aware Antibody Design (RAAD) framework, which dynamically models antigen-antibody interactions for co-designing the sequences and structures of antigen-specific CDRs. Furthermore, we propose a new evaluation metric to better measure antibody specificity and develop a contrasting specificity-enhancing constraint to optimize the specificity of antibodies. Extensive experiments have demonstrated the superior capability of RAAD in terms of antibody modeling, generation, and optimization across different CDR types, sequence lengths, pre-training strategies, and input contexts.

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ICLR Conference 2025 Conference Paper

ReNovo: Retrieval-Based \emph{De Novo} Mass Spectrometry Peptide Sequencing

  • Shaorong Chen
  • Jun Xia 0001
  • Jingbo Zhou
  • Lecheng Zhang
  • Zhangyang Gao
  • Bozhen Hu
  • Cheng Tan 0012
  • Wenjie Du 0003

Proteomics is the large-scale study of proteins. Tandem mass spectrometry, as the only high-throughput technique for protein sequence identification, plays a pivotal role in proteomics research. One of the long-standing challenges in this field is peptide identification, which entails determining the specific peptide (sequence of amino acids) that corresponds to each observed mass spectrum. The conventional approach involves database searching, wherein the observed mass spectrum is scored against a pre-constructed peptide database. However, the reliance on pre-existing databases limits applicability in scenarios where the peptide is absent from existing databases. Such circumstances necessitate \emph{de novo} peptide sequencing, which derives peptide sequence solely from input mass spectrum, independent of any peptide database. Despite ongoing advancements in \emph{de novo} peptide sequencing, its performance still has considerable room for improvement, which limits its application in large-scale experiments. In this study, we introduce a novel \textbf{Re}trieval-based \emph{De \textbf{Novo}} peptide sequencing methodology, termed \textbf{ReNovo}, which draws inspiration from database search methods. Specifically, by constructing a datastore from training data, ReNovo can retrieve information from the datastore during the inference stage to conduct retrieval-based inference, thereby achieving improved performance. This innovative approach enables ReNovo to effectively combine the strengths of both methods: utilizing the assistance of the datastore while also being capable of predicting novel peptides that are not present in pre-existing databases. A series of experiments have confirmed that ReNovo outperforms state-of-the-art models across multiple widely-used datasets, incurring only minor storage and time consumption, representing a significant advancement in proteomics. Supplementary materials include the code.

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IJCAI Conference 2025 Conference Paper

SketchAgent: Generating Structured Diagrams from Hand-Drawn Sketches

  • Cheng Tan
  • Qi Chen
  • Jingxuan Wei
  • Gaowei Wu
  • Zhangyang Gao
  • Siyuan Li
  • Bihui Yu
  • Ruifeng Guo

Hand-drawn sketches are a natural and efficient medium for capturing and conveying ideas. Despite significant advancements in controllable natural image generation, translating freehand sketches into structured, machine-readable diagrams remains a labor-intensive and predominantly manual task. The primary challenge stems from the inherent ambiguity of sketches, which lack the structural constraints and semantic precision required for automated diagram generation. To address this challenge, we introduce SketchAgent, a multi-agent system designed to automate the transformation of hand-drawn sketches into structured diagrams. SketchAgent integrates sketch recognition, symbolic reasoning, and iterative validation to produce semantically coherent and structurally accurate diagrams, significantly reducing the need for manual effort. To evaluate the effectiveness of our approach, we propose the Sketch2Diagram Benchmark, a comprehensive dataset and evaluation framework encompassing eight diverse diagram categories, such as flowcharts, directed graphs, and model architectures. The dataset comprises over 6, 000 high-quality examples with token-level annotations, standardized preprocessing, and rigorous quality control. By streamlining the diagram generation process, SketchAgent holds great promise for applications in design, education, and engineering, while offering a significant step toward bridging the gap between intuitive sketching and machine-readable diagram generation.

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ICML Conference 2024 Conference Paper

A Graph is Worth K Words: Euclideanizing Graph using Pure Transformer

  • Zhangyang Gao
  • Daize Dong
  • Cheng Tan 0012
  • Jun Xia 0001
  • Bozhen Hu
  • Stan Z. Li

Can we model Non-Euclidean graphs as pure language or even Euclidean vectors while retaining their inherent information? The Non-Euclidean property have posed a long term challenge in graph modeling. Despite recent graph neural networks and graph transformers efforts encoding graphs as Euclidean vectors, recovering the original graph from vectors remains a challenge. In this paper, we introduce GraphsGPT, featuring an Graph2Seq encoder that transforms Non-Euclidean graphs into learnable Graph Words in the Euclidean space, along with a GraphGPT decoder that reconstructs the original graph from Graph Words to ensure information equivalence. We pretrain GraphsGPT on $100$M molecules and yield some interesting findings: (1) The pretrained Graph2Seq excels in graph representation learning, achieving state-of-the-art results on $8/9$ graph classification and regression tasks. (2) The pretrained GraphGPT serves as a strong graph generator, demonstrated by its strong ability to perform both few-shot and conditional graph generation. (3) Graph2Seq+GraphGPT enables effective graph mixup in the Euclidean space, overcoming previously known Non-Euclidean challenges. (4) The edge-centric pretraining framework GraphsGPT demonstrates its efficacy in graph domain tasks, excelling in both representation and generation. Code is available at https: //github. com/A4Bio/GraphsGPT.

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NeurIPS Conference 2024 Conference Paper

AdaNovo: Towards Robust \emph{De Novo} Peptide Sequencing in Proteomics against Data Biases

  • Jun Xia
  • Shaorong Chen
  • Jingbo Zhou
  • Xiaojun Shan
  • Wenjie Du
  • Zhangyang Gao
  • Cheng Tan
  • Bozhen Hu

Tandem mass spectrometry has played a pivotal role in advancing proteomics, enabling the high-throughput analysis of protein composition in biological tissues. Despite the development of several deep learning methods for predicting amino acid sequences (peptides) responsible for generating the observed mass spectra, training data biases hinder further advancements of \emph{de novo} peptide sequencing. Firstly, prior methods struggle to identify amino acids with Post-Translational Modifications (PTMs) due to their lower frequency in training data compared to canonical amino acids, further resulting in unsatisfactory peptide sequencing performance. Secondly, various noise and missing peaks in mass spectra reduce the reliability of training data (Peptide-Spectrum Matches, PSMs). To address these challenges, we propose AdaNovo, a novel and domain knowledge-inspired framework that calculates Conditional Mutual Information (CMI) between the mass spectra and amino acids or peptides, using CMI for robust training against above biases. Extensive experiments indicate that AdaNovo outperforms previous competitors on the widely-used 9-species benchmark, meanwhile yielding 3. 6\% - 9. 4\% improvements in PTMs identification. The supplements contain the code.

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AAAI Conference 2024 Conference Paper

Cross-Gate MLP with Protein Complex Invariant Embedding Is a One-Shot Antibody Designer

  • Cheng Tan
  • Zhangyang Gao
  • Lirong Wu
  • Jun Xia
  • Jiangbin Zheng
  • Xihong Yang
  • Yue Liu
  • Bozhen Hu

Antibodies are crucial proteins produced by the immune system in response to foreign substances or antigens. The specificity of an antibody is determined by its complementarity-determining regions (CDRs), which are located in the variable domains of the antibody chains and form the antigen-binding site. Previous studies have utilized complex techniques to generate CDRs, but they suffer from inadequate geometric modeling. Moreover, the common iterative refinement strategies lead to an inefficient inference. In this paper, we propose a simple yet effective model that can co-design 1D sequences and 3D structures of CDRs in a one-shot manner. To achieve this, we decouple the antibody CDR design problem into two stages: (i) geometric modeling of protein complex structures and (ii) sequence-structure co-learning. We develop a novel macromolecular structure invariant embedding, typically for protein complexes, that captures both intra- and inter-component interactions among the backbone atoms, including Calpha, N, C, and O atoms, to achieve comprehensive geometric modeling. Then, we introduce a simple cross-gate MLP for sequence-structure co-learning, allowing sequence and structure representations to implicitly refine each other. This enables our model to design desired sequences and structures in a one-shot manner. Extensive experiments are conducted to evaluate our results at both the sequence and structure level, which demonstrate that our model achieves superior performance compared to the state-of-the-art antibody CDR design methods.

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ICML Conference 2024 Conference Paper

Deciphering RNA Secondary Structure Prediction: A Probabilistic K-Rook Matching Perspective

  • Cheng Tan 0012
  • Zhangyang Gao
  • Hanqun Cao
  • Xingran Chen
  • Ge Wang
  • Lirong Wu
  • Jun Xia 0001
  • Jiangbin Zheng 0002

The secondary structure of ribonucleic acid (RNA) is more stable and accessible in the cell than its tertiary structure, making it essential for functional prediction. Although deep learning has shown promising results in this field, current methods suffer from poor generalization and high complexity. In this work, we reformulate the RNA secondary structure prediction as a K-Rook problem, thereby simplifying the prediction process into probabilistic matching within a finite solution space. Building on this innovative perspective, we introduce RFold, a simple yet effective method that learns to predict the most matching K-Rook solution from the given sequence. RFold employs a bi-dimensional optimization strategy that decomposes the probabilistic matching problem into row-wise and column-wise components to reduce the matching complexity, simplifying the solving process while guaranteeing the validity of the output. Extensive experiments demonstrate that RFold achieves competitive performance and about eight times faster inference efficiency than the state-of-the-art approaches. The code is available at https: //github. com/A4Bio/RFold.

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ICLR Conference 2024 Conference Paper

Decoupling Weighing and Selecting for Integrating Multiple Graph Pre-training Tasks

  • Tianyu Fan
  • Lirong Wu
  • Yufei Huang 0002
  • Haitao Lin
  • Cheng Tan 0012
  • Zhangyang Gao
  • Stan Z. Li

Recent years have witnessed the great success of graph pre-training for graph representation learning. With hundreds of graph pre-training tasks proposed, integrating knowledge acquired from multiple pre-training tasks has become a popular research topic. In this paper, we identify two important collaborative processes for this topic: (1) select: how to select an optimal task combination from a given task pool based on their compatibility, and (2) weigh: how to weigh the selected tasks based on their importance. While there currently has been a lot of work focused on weighing, comparatively little effort has been devoted to selecting. This paper proposes a novel instance-level framework for integrating multiple graph pre-training tasks, Weigh And Select (WAS), where the two collaborative processes, weighing and selecting, are combined by decoupled siamese networks. Specifically, it first adaptively learns an optimal combination of tasks for each instance from a given task pool, based on which a customized instance-level task weighing strategy is learned. Extensive experiments on 16 graph datasets across node-level and graph-level downstream tasks have demonstrated that by combining a few simple but classical tasks, WAS can achieve comparable performance to other leading counterparts. The code is available at https://github.com/TianyuFan0504/WAS.

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NeurIPS Conference 2024 Conference Paper

Deep Graph Neural Networks via Posteriori-Sampling-based Node-Adaptative Residual Module

  • Jingbo Zhou
  • Yixuan Du
  • Ruqiong Zhang
  • Jun Xia
  • Zhizhi Yu
  • Zelin Zang
  • Di Jin
  • Carl Yang

Graph Neural Networks (GNNs), a type of neural network that can learn from graph-structured data through neighborhood information aggregation, have shown superior performance in various downstream tasks. However, as the number of layers increases, node representations becomes indistinguishable, which is known as over-smoothing. To address this issue, many residual methods have emerged. In this paper, we focus on the over-smoothing issue and related residual methods. Firstly, we revisit over-smoothing from the perspective of overlapping neighborhood subgraphs, and based on this, we explain how residual methods can alleviate over-smoothing by integrating multiple orders neighborhood subgraphs to avoid the indistinguishability of the single high-order neighborhood subgraphs. Additionally, we reveal the drawbacks of previous residual methods, such as the lack of node adaptability and severe loss of high-order neighborhood subgraph information, and propose a \textbf{Posterior-Sampling-based, Node-Adaptive Residual module (PSNR)}. We theoretically demonstrate that PSNR can alleviate the drawbacks of previous residual methods. Furthermore, extensive experiments verify the superiority of the PSNR module in fully observed node classification and missing feature scenarios. Our codeis available at \href{https: //github. com/jingbo02/PSNR-GNN}{https: //github. com/jingbo02/PSNR-GNN}.

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ICML Conference 2024 Conference Paper

DiffAug: Enhance Unsupervised Contrastive Learning with Domain-Knowledge-Free Diffusion-based Data Augmentation

  • Zelin Zang
  • Hao Luo 0004
  • Kai Wang 0036
  • Panpan Zhang
  • Fan Wang 0019
  • Stan Z. Li
  • Yang You 0001

Unsupervised Contrastive learning has gained prominence in fields such as vision, and biology, leveraging predefined positive/negative samples for representation learning. Data augmentation, categorized into hand-designed and model-based methods, has been identified as a crucial component for enhancing contrastive learning. However, hand-designed methods require human expertise in domain-specific data while sometimes distorting the meaning of the data. In contrast, generative model-based approaches usually require supervised or large-scale external data, which has become a bottleneck constraining model training in many domains. To address the problems presented above, this paper proposes DiffAug, a novel unsupervised contrastive learning technique with diffusion mode-based positive data generation. DiffAug consists of a semantic encoder and a conditional diffusion model; the conditional diffusion model generates new positive samples conditioned on the semantic encoding to serve the training of unsupervised contrast learning. With the help of iterative training of the semantic encoder and diffusion model, DiffAug improves the representation ability in an uninterrupted and unsupervised manner. Experimental evaluations show that DiffAug outperforms hand-designed and SOTA model-based augmentation methods on DNA sequence, visual, and bio-feature datasets. The code for review is released at DiffAug CODE.

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NeurIPS Conference 2024 Conference Paper

FlexMol: A Flexible Toolkit for Benchmarking Molecular Relational Learning

  • Sizhe Liu
  • Jun Xia
  • Lecheng Zhang
  • Yuchen Liu
  • Yue Liu
  • Wenjie Du
  • Zhangyang Gao
  • Bozhen Hu

Molecular relational learning (MRL) is crucial for understanding the interaction behaviors between molecular pairs, a critical aspect of drug discovery and development. However, the large feasible model space of MRL poses significant challenges to benchmarking, and existing MRL frameworks face limitations in flexibility and scope. To address these challenges, avoid repetitive coding efforts, and ensure fair comparison of models, we introduce FlexMol, a comprehensive toolkit designed to facilitate the construction and evaluation of diverse model architectures across various datasets and performance metrics. FlexMol offers a robust suite of preset model components, including 16 drug encoders, 13 protein sequence encoders, 9 protein structure encoders, and 7 interaction layers. With its easy-to-use API and flexibility, FlexMol supports the dynamic construction of over 70, 000 distinct combinations of model architectures. Additionally, we provide detailed benchmark results and code examples to demonstrate FlexMol’s effectiveness in simplifying and standardizing MRL model development and comparison. FlexMol is open-sourced and available at https: //github. com/Steven51516/FlexMol.

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ICML Conference 2024 Conference Paper

GeoAB: Towards Realistic Antibody Design and Reliable Affinity Maturation

  • Haitao Lin
  • Lirong Wu
  • Yufei Huang 0002
  • Yunfan Liu 0002
  • Odin Zhang
  • Yuanqing Zhou
  • Rui Sun
  • Stan Z. Li

Increasing works for antibody design are emerging to generate sequences and structures in Complementarity Determining Regions (CDRs), but problems still exist. We focus on two of them: (i) authenticity of the generated structure and (ii) rationality of the affinity maturation, and propose GeoAB as a solution. In specific, GeoAB-Designergenerates CDR structures with realistic internal geometries, composed of a generative geometry initializer (Geo-Initializer) and a position refiner (Geo-Refiner); GeoAB-Optimizer achieves affinity maturation by accurately predicting both the mutation effects and structures of mutant antibodies with the same network architecture as Geo-Refiner. Experiments show that GeoAB achieves state-of-the-art performance in CDR co-design and mutation effect predictions, and fulfills the discussed tasks effectively.

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NeurIPS Conference 2024 Conference Paper

Instructor-inspired Machine Learning for Robust Molecular Property Prediction

  • Fang Wu
  • Shuting Jin
  • Siyuan Li
  • Stan Z. Li

Machine learning catalyzes a revolution in chemical and biological science. However, its efficacy is heavily dependent on the availability of labeled data, and annotating biochemical data is extremely laborious. To surmount this data sparsity challenge, we present an instructive learning algorithm named InstructMol to measure pseudo-labels' reliability and help the target model leverage large-scale unlabeled data. InstructMol does not require transferring knowledge between multiple domains, which avoids the potential gap between the pretraining and fine-tuning stages. We demonstrated the high accuracy of InstructMol on several real-world molecular datasets and out-of-distribution (OOD) benchmarks.

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ICLR Conference 2024 Conference Paper

KW-Design: Pushing the Limit of Protein Design via Knowledge Refinement

  • Zhangyang Gao
  • Cheng Tan 0012
  • Xingran Chen
  • Yijie Zhang
  • Jun Xia 0001
  • Siyuan Li 0002
  • Stan Z. Li

Recent studies have shown competitive performance in protein inverse folding, while most of them disregard the importance of predictive confidence, fail to cover the vast protein space, and do not incorporate common protein knowledge. Given the great success of pretrained models on diverse protein-related tasks and the fact that recovery is highly correlated with confidence, we wonder whether this knowledge can push the limits of protein design further. As a solution, we propose a knowledge-aware module that refines low-quality residues. We also introduce a memory-retrieval mechanism to save more than 50\% of the training time. We extensively evaluate our proposed method on the CATH, TS50, TS500, and PDB datasets and our results show that our KW-Design method outperforms the previous PiFold method by approximately 9\% on the CATH dataset. KW-Design is the first method that achieves 60+\% recovery on all these benchmarks. We also provide additional analysis to demonstrate the effectiveness of our proposed method. The code is publicly available via \href{https://github.com/A4Bio/ProteinInvBench}{GitHub}.

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NeurIPS Conference 2024 Conference Paper

Learning Complete Protein Representation by Dynamically Coupling of Sequence and Structure

  • Bozhen Hu
  • Cheng Tan
  • Jun Xia
  • Yue Liu
  • Lirong Wu
  • Jiangbin Zheng
  • Yongjie Xu
  • Yufei Huang

Learning effective representations is imperative for comprehending proteins and deciphering their biological functions. Recent strides in language models and graph neural networks have empowered protein models to harness primary or tertiary structure information for representation learning. Nevertheless, the absence of practical methodologies to appropriately model intricate inter-dependencies between protein sequences and structures has resulted in embeddings that exhibit low performance on tasks such as protein function prediction. In this study, we introduce CoupleNet, a novel framework designed to interlink protein sequences and structures to derive informative protein representations. CoupleNet integrates multiple levels and scales of features in proteins, encompassing residue identities and positions for sequences, as well as geometric representations for tertiary structures from both local and global perspectives. A two-type dynamic graph is constructed to capture adjacent and distant sequential features and structural geometries, achieving completeness at the amino acid and backbone levels. Additionally, convolutions are executed on nodes and edges simultaneously to generate comprehensive protein embeddings. Experimental results on benchmark datasets showcase that CoupleNet outperforms state-of-the-art methods, exhibiting particularly superior performance in low-sequence similarities scenarios, adeptly identifying infrequently encountered functions and effectively capturing remote homology relationships in proteins.

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ICML Conference 2024 Conference Paper

Learning to Predict Mutational Effects of Protein-Protein Interactions by Microenvironment-aware Hierarchical Prompt Learning

  • Lirong Wu
  • Yijun Tian 0001
  • Haitao Lin
  • Yufei Huang 0002
  • Siyuan Li 0002
  • Nitesh V. Chawla
  • Stan Z. Li

Protein-protein bindings play a key role in a variety of fundamental biological processes, and thus predicting the effects of amino acid mutations on protein-protein binding is crucial. To tackle the scarcity of annotated mutation data, pre-training with massive unlabeled data has emerged as a promising solution. However, this process faces a series of challenges: (1) complex higher-order dependencies among multiple (more than paired) structural scales have not yet been fully captured; (2) it is rarely explored how mutations alter the local conformation of the surrounding microenvironment; (3) pre-training is costly, both in data size and computational burden. In this paper, we first construct a hierarchical prompt codebook to record common microenvironmental patterns at different structural scales independently. Then, we develop a novel codebook pre-training task, namely masked microenvironment modeling, to model the joint distribution of each mutation with their residue types, angular statistics, and local conformational changes in the microenvironment. With the constructed prompt codebook, we encode the microenvironment around each mutation into multiple hierarchical prompts and combine them to flexibly provide information to wild-type and mutated protein complexes about their microenvironmental differences. Such a hierarchical prompt learning framework has demonstrated superior performance and training efficiency over state-of-the-art pre-training-based methods in mutation effect prediction and a case study of optimizing human antibodies against SARS-CoV-2.

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IJCAI Conference 2024 Conference Paper

LongVQ: Long Sequence Modeling with Vector Quantization on Structured Memory

  • Zicheng Liu
  • Li Wang
  • Siyuan Li
  • Zedong Wang
  • Haitao Lin
  • Stan Z. Li

Transformer models have been successful in various sequence processing tasks, but the self-attention mechanism's computational cost limits its practicality for long sequences. Although there are existing attention variants that improve computational efficiency, they have a limited ability to abstract global information effectively based on their hand-crafted mixing strategies. On the other hand, state-space models (SSMs) are tailored for long sequences but cannot capture complicated local information. Therefore, the combination of them as a unified token mixer is a trend in recent long-sequence models. However, the linearized attention degrades performance significantly even when equipped with SSMs. To address the issue, we propose a new method called LongVQ. LongVQ uses the vector quantization (VQ) technique to compress the global abstraction as a length-fixed codebook, enabling the linear-time computation of the attention matrix. This technique effectively maintains dynamic global and local patterns, which helps to complement the lack of long-range dependency issues. Our experiments on the Long Range Arena benchmark, autoregressive language modeling, and image and speech classification demonstrate the effectiveness of LongVQ. Our model achieves significant improvements over other sequence models, including variants of Transformers, Convolutions, and recent State Space Models.

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ICLR Conference 2024 Conference Paper

MAPE-PPI: Towards Effective and Efficient Protein-Protein Interaction Prediction via Microenvironment-Aware Protein Embedding

  • Lirong Wu
  • Yijun Tian 0001
  • Yufei Huang 0002
  • Siyuan Li 0002
  • Haitao Lin
  • Nitesh V. Chawla
  • Stan Z. Li

Protein-Protein Interactions (PPIs) are fundamental in various biological processes and play a key role in life activities. The growing demand and cost of experimental PPI assays require computational methods for efficient PPI prediction. While existing methods rely heavily on protein sequence for PPI prediction, it is the protein structure that is the key to determine the interactions. To take both protein modalities into account, we define the microenvironment of an amino acid residue by its sequence and structural contexts, which describe the surrounding chemical properties and geometric features. In addition, microenvironments defined in previous work are largely based on experimentally assayed physicochemical properties, for which the "vocabulary" is usually extremely small. This makes it difficult to cover the diversity and complexity of microenvironments. In this paper, we propose Microenvironment-Aware Protein Embedding for PPI prediction (MPAE-PPI), which encodes microenvironments into chemically meaningful discrete codes via a sufficiently large microenvironment "vocabulary" (i.e., codebook). Moreover, we propose a novel pre-training strategy, namely Masked Codebook Modeling (MCM), to capture the dependencies between different microenvironments by randomly masking the codebook and reconstructing the input. With the learned microenvironment codebook, we can reuse it as an off-the-shelf tool to efficiently and effectively encode proteins of different sizes and functions for large-scale PPI prediction. Extensive experiments show that MAPE-PPI can scale to PPI prediction with millions of PPIs with superior trade-offs between effectiveness and computational efficiency than the state-of-the-art competitors.

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ICLR Conference 2024 Conference Paper

MogaNet: Multi-order Gated Aggregation Network

  • Siyuan Li 0002
  • Zedong Wang
  • Zicheng Liu 0006
  • Cheng Tan 0012
  • Haitao Lin
  • Di Wu 0057
  • Zhiyuan Chen 0008
  • Jiangbin Zheng 0002

By contextualizing the kernel as global as possible, Modern ConvNets have shown great potential in computer vision tasks. However, recent progress on \textit{multi-order game-theoretic interaction} within deep neural networks (DNNs) reveals the representation bottleneck of modern ConvNets, where the expressive interactions have not been effectively encoded with the increased kernel size. To tackle this challenge, we propose a new family of modern ConvNets, dubbed MogaNet, for discriminative visual representation learning in pure ConvNet-based models with favorable complexity-performance trade-offs. MogaNet encapsulates conceptually simple yet effective convolutions and gated aggregation into a compact module, where discriminative features are efficiently gathered and contextualized adaptively. MogaNet exhibits great scalability, impressive efficiency of parameters, and competitive performance compared to state-of-the-art ViTs and ConvNets on ImageNet and various downstream vision benchmarks, including COCO object detection, ADE20K semantic segmentation, 2D\&3D human pose estimation, and video prediction. Notably, MogaNet hits 80.0\% and 87.8\% accuracy with 5.2M and 181M parameters on ImageNet-1K, outperforming ParC-Net and ConvNeXt-L, while saving 59\% FLOPs and 17M parameters, respectively. The source code is available at https://github.com/Westlake-AI/MogaNet.

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NeurIPS Conference 2024 Conference Paper

NovoBench: Benchmarking Deep Learning-based \emph{De Novo} Sequencing Methods in Proteomics

  • Jingbo Zhou
  • Shaorong Chen
  • Jun Xia
  • Sizhe Sizhe Liu
  • Tianze Ling
  • Wenjie Du
  • Yue Liu
  • Jianwei Yin

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

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NeurIPS Conference 2024 Conference Paper

PhyloGen: Language Model-Enhanced Phylogenetic Inference via Graph Structure Generation

  • ChenRui Duan
  • Zelin Zang
  • Siyuan Li
  • Yongjie Xu
  • Stan Z. Li

Phylogenetic trees elucidate evolutionary relationships among species, but phylogenetic inference remains challenging due to the complexity of combining continuous (branch lengths) and discrete parameters (tree topology). Traditional Markov Chain Monte Carlo methods face slow convergence and computational burdens. Existing Variational Inference methods, which require pre-generated topologies and typically treat tree structures and branch lengths independently, may overlook critical sequence features, limiting their accuracy and flexibility. We propose PhyloGen, a novel method leveraging a pre-trained genomic language model to generate and optimize phylogenetic trees without dependence on evolutionary models or aligned sequence constraints. PhyloGen views phylogenetic inference as a conditionally constrained tree structure generation problem, jointly optimizing tree topology and branch lengths through three core modules: (i) Feature Extraction, (ii) PhyloTree Construction, and (iii) PhyloTree Structure Modeling. Meanwhile, we introduce a Scoring Function to guide the model towards a more stable gradient descent. We demonstrate the effectiveness and robustness of PhyloGen on eight real-world benchmark datasets. Visualization results confirm PhyloGen provides deeper insights into phylogenetic relationships.

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ICML Conference 2024 Conference Paper

PPFLOW: Target-Aware Peptide Design with Torsional Flow Matching

  • Haitao Lin
  • Odin Zhang
  • Huifeng Zhao
  • Dejun Jiang 0002
  • Lirong Wu
  • Zicheng Liu 0006
  • Yufei Huang 0002
  • Stan Z. Li

Therapeutic peptides have proven to have great pharmaceutical value and potential in recent decades. However, methods of AI-assisted peptide drug discovery are not fully explored. To fill the gap, we propose a target-aware peptide design method called PPFlow, based on conditional flow matching on torus manifolds, to model the internal geometries of torsion angles for the peptide structure design. Besides, we establish a protein-peptide binding dataset named PPBench2024 to fill the void of massive data for the task of structure-based peptide drug design and to allow the training of deep learning methods. Extensive experiments show that PPFlow reaches state-of-the-art performance in tasks of peptide drug generation and optimization in comparison with baseline models, and can be generalized to other tasks including docking and side-chain packing.

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AAAI Conference 2024 Conference Paper

Protein 3D Graph Structure Learning for Robust Structure-Based Protein Property Prediction

  • Yufei Huang
  • Siyuan Li
  • Lirong Wu
  • Jin Su
  • Haitao Lin
  • Odin Zhang
  • Zihan Liu
  • Zhangyang Gao

Protein structure-based property prediction has emerged as a promising approach for various biological tasks, such as protein function prediction and sub-cellular location estimation. The existing methods highly rely on experimental protein structure data and fail in scenarios where these data are unavailable. Predicted protein structures from AI tools (e.g., AlphaFold2) were utilized as alternatives. However, we observed that current practices, which simply employ accurately predicted structures during inference, suffer from notable degradation in prediction accuracy. While similar phenomena have been extensively studied in general fields (e.g., Computer Vision) as model robustness, their impact on protein property prediction remains unexplored. In this paper, we first investigate the reason behind the performance decrease when utilizing predicted structures, attributing it to the structure embedding bias from the perspective of structure representation learning. To study this problem, we identify a Protein 3D Graph Structure Learning Problem for Robust Protein Property Prediction (PGSL-RP3), collect benchmark datasets, and present a protein Structure embedding Alignment Optimization framework (SAO) to mitigate the problem of structure embedding bias between the predicted and experimental protein structures. Extensive experiments have shown that our framework is model-agnostic and effective in improving the property prediction of both predicted structures and experimental structures.

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NeurIPS Conference 2024 Conference Paper

ProtGO: Function-Guided Protein Modeling for Unified Representation Learning

  • Bozhen Hu
  • Cheng Tan
  • Yongjie Xu
  • Zhangyang Gao
  • Jun Xia
  • Lirong Wu
  • Stan Z. Li

Protein representation learning is indispensable for various downstream applications of artificial intelligence for bio-medicine research, such as drug design and function prediction. However, achieving effective representation learning for proteins poses challenges due to the diversity of data modalities involved, including sequence, structure, and function annotations. Despite the impressive capabilities of large language models in biomedical text modelling, there remains a pressing need for a framework that seamlessly integrates these diverse modalities, particularly focusing on the three critical aspects of protein information: sequence, structure, and function. Moreover, addressing the inherent data scale differences among these modalities is essential. To tackle these challenges, we introduce ProtGO, a unified model that harnesses a teacher network equipped with a customized graph neural network (GNN) and a Gene Ontology (GO) encoder to learn hybrid embeddings. Notably, our approach eliminates the need for additional functions as input for the student network, which shares the same GNN module. Importantly, we utilize a domain adaptation method to facilitate distribution approximation for guiding the training of the teacher-student framework. This approach leverages distributions learned from latent representations to avoid the alignment of individual samples. Benchmark experiments highlight that ProtGO significantly outperforms state-of-the-art baselines, clearly demonstrating the advantages of the proposed unified framework.

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AAAI Conference 2024 Conference Paper

PSC-CPI: Multi-Scale Protein Sequence-Structure Contrasting for Efficient and Generalizable Compound-Protein Interaction Prediction

  • Lirong Wu
  • Yufei Huang
  • Cheng Tan
  • Zhangyang Gao
  • Bozhen Hu
  • Haitao Lin
  • Zicheng Liu
  • Stan Z. Li

Compound-Protein Interaction (CPI) prediction aims to predict the pattern and strength of compound-protein interactions for rational drug discovery. Existing deep learning-based methods utilize only the single modality of protein sequences or structures and lack the co-modeling of the joint distribution of the two modalities, which may lead to significant performance drops in complex real-world scenarios due to various factors, e.g., modality missing and domain shifting. More importantly, these methods only model protein sequences and structures at a single fixed scale, neglecting more fine-grained multi-scale information, such as those embedded in key protein fragments. In this paper, we propose a novel multi-scale Protein Sequence-structure Contrasting framework for CPI prediction (PSC-CPI), which captures the dependencies between protein sequences and structures through both intra-modality and cross-modality contrasting. We further apply length-variable protein augmentation to allow contrasting to be performed at different scales, from the amino acid level to the sequence level. Finally, in order to more fairly evaluate the model generalizability, we split the test data into four settings based on whether compounds and proteins have been observed during the training stage. Extensive experiments have shown that PSC-CPI generalizes well in all four settings, particularly in the more challenging ``Unseen-Both" setting, where neither compounds nor proteins have been observed during training. Furthermore, even when encountering a situation of modality missing, i.e., inference with only single-modality protein data, PSC-CPI still exhibits comparable or even better performance than previous approaches.

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ICLR Conference 2024 Conference Paper

RDesign: Hierarchical Data-efficient Representation Learning for Tertiary Structure-based RNA Design

  • Cheng Tan 0012
  • Yijie Zhang
  • Zhangyang Gao
  • Bozhen Hu
  • Siyuan Li 0002
  • Zicheng Liu 0006
  • Stan Z. Li

While artificial intelligence has made remarkable strides in revealing the relationship between biological macromolecules' primary sequence and tertiary structure, designing RNA sequences based on specified tertiary structures remains challenging. Though existing approaches in protein design have thoroughly explored structure-to-sequence dependencies in proteins, RNA design still confronts difficulties due to structural complexity and data scarcity. Moreover, direct transplantation of protein design methodologies into RNA design fails to achieve satisfactory outcomes although sharing similar structural components. In this study, we aim to systematically construct a data-driven RNA design pipeline. We crafted a large, well-curated benchmark dataset and designed a comprehensive structural modeling approach to represent the complex RNA tertiary structure. More importantly, we proposed a hierarchical data-efficient representation learning framework that learns structural representations through contrastive learning at both cluster-level and sample-level to fully leverage the limited data. By constraining data representations within a limited hyperspherical space, the intrinsic relationships between data points could be explicitly imposed. Moreover, we incorporated extracted secondary structures with base pairs as prior knowledge to facilitate the RNA design process. Extensive experiments demonstrate the effectiveness of our proposed method, providing a reliable baseline for future RNA design tasks. The source code and benchmark dataset are available at https://github.com/A4Bio/RDesign.

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ICML Conference 2024 Conference Paper

Re-Dock: Towards Flexible and Realistic Molecular Docking with Diffusion Bridge

  • Yufei Huang 0002
  • Odin Zhang
  • Lirong Wu
  • Cheng Tan 0012
  • Haitao Lin
  • Zhangyang Gao
  • Siyuan Li 0002
  • Stan Z. Li

Accurate prediction of protein-ligand binding structures, a task known as molecular docking is crucial for drug design but remains challenging. While deep learning has shown promise, existing methods often depend on holo-protein structures (docked, and not accessible in realistic tasks) or neglect pocket sidechain conformations, leading to limited practical utility and unrealistic conformation predictions. To fill these gaps, we introduce an under-explored task, named flexible docking to predict poses of ligand and pocket sidechains simultaneously and introduce Re-Dock, a novel diffusion bridge generative model extended to geometric manifolds. Specifically, we propose energy-to-geometry mapping inspired by the Newton-Euler equation to co-model the binding energy and conformations for reflecting the energy-constrained docking generative process. Comprehensive experiments on designed benchmark datasets including apo-dock and cross-dock demonstrate our model’s superior effectiveness and efficiency over current methods.

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ICLR Conference 2024 Conference Paper

SemiReward: A General Reward Model for Semi-supervised Learning

  • Siyuan Li 0002
  • Weiyang Jin
  • Zedong Wang
  • Fang Wu 0002
  • Zicheng Liu 0006
  • Cheng Tan 0012
  • Stan Z. Li

Semi-supervised learning (SSL) has witnessed great progress with various improvements in the self-training framework with pseudo labeling. The main challenge is how to distinguish high-quality pseudo labels against the confirmation bias. However, existing pseudo-label selection strategies are limited to pre-defined schemes or complex hand-crafted policies specially designed for classification, failing to achieve high-quality labels, fast convergence, and task versatility simultaneously. To these ends, we propose a Semi-supervised Reward framework (SemiReward) that predicts reward scores to evaluate and filter out high-quality pseudo labels, which is pluggable to mainstream SSL methods in wide task types and scenarios. To mitigate confirmation bias, SemiReward is trained online in two stages with a generator model and subsampling strategy. With classification and regression tasks on 13 standard SSL benchmarks across three modalities, extensive experiments verify that SemiReward achieves significant performance gains and faster convergence speeds upon Pseudo Label, FlexMatch, and Free/SoftMatch. Code and models are available at https://github.com/Westlake-AI/SemiReward.

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ICML Conference 2024 Conference Paper

Short-Long Convolutions Help Hardware-Efficient Linear Attention to Focus on Long Sequences

  • Zicheng Liu 0006
  • Siyuan Li 0002
  • Li Wang
  • Zedong Wang
  • Yunfan Liu 0002
  • Stan Z. Li

To mitigate the computational complexity in the self-attention mechanism on long sequences, linear attention utilizes computation tricks to achieve linear complexity, while state space models (SSMs) popularize a favourable practice of using non-data-dependent memory pattern, i. e. , emphasize the near and neglect the distant, to processing sequences. Recent studies have shown the priorities by combining them as one. However, the efficiency of linear attention remains only at the theoretical level in a causal setting, and SSMs require various designed constraints to operate effectively on specific data. Therefore, in order to unveil the true power of the hybrid design, the following two issues need to be addressed: (1) hardware-efficient implementation for linear attention and (2) stabilization of SSMs. To achieve this, we leverage the thought of tiling and hierarchy to propose CHELA (short-long Convolutions with Hardware-Efficient Linear Attention), which replaces SSMs with short-long convolutions and implements linear attention in a divide-and-conquer manner. This approach enjoys global abstraction and data-dependent selection from stable SSM and linear attention while maintaining real linear complexity. Our comprehensive experiments on the Long Range Arena benchmark and language modeling tasks demonstrate the effectiveness of the proposed method.

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ICML Conference 2024 Conference Paper

Surface-VQMAE: Vector-quantized Masked Auto-encoders on Molecular Surfaces

  • Fang Wu 0002
  • Stan Z. Li

Molecular surfaces imply fingerprints of interaction patterns between proteins. However, non-equivalent efforts have been paid to incorporating the abundant protein surface information for analyzing proteins’ biological functions in juxtaposition to amino acid sequences and 3D structures. We propose a novel surface-based unsupervised learning algorithm termed Surface-VQMAE to overcome this obstacle. In light of surface point clouds’ sparsity and disorder properties, we first partition them into patches and obtain the sequential arrangement via the Morton curve. Successively, a Transformer-based architecture named SurfFormer was introduced to integrate the surface geometry and capture patch-level relations. At last, we enhance the prevalent masked auto-encoder (MAE) with the vector quantization (VQ) technique, which establishes a surface pattern codebook to enforce a discrete posterior distribution of latent variables and achieve more condensed semantics. Our work is the foremost to implement pretraining purely on molecular surfaces and extensive experiments on diverse real-life scenarios including binding site scoring, binding affinity prediction, and mutant effect estimation demonstrate its effectiveness. The code is available at https: //github. com/smiles724/VQMAE.

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NeurIPS Conference 2024 Conference Paper

UniIF: Unified Molecule Inverse Folding

  • Zhangyang Gao
  • Jue Wang
  • Cheng Tan
  • Lirong Wu
  • Yufei Huang
  • Siyuan Li
  • Zhirui Ye
  • Stan Z. Li

Molecule inverse folding has been a long-standing challenge in chemistry and biology, with the potential to revolutionize drug discovery and material science. Despite specified models have been proposed for different small- or macro-molecules, few have attempted to unify the learning process, resulting in redundant efforts. Complementary to recent advancements in molecular structure prediction, such as RoseTTAFold All-Atom and AlphaFold3, we propose the unified model UniIF for the inverse folding of all molecules. We do such unification in two levels: 1) Data-Level: We propose a unified block graph data form for all molecules, including the local frame building and geometric feature initialization. 2) Model-Level: We introduce a geometric block attention network, comprising a geometric interaction, interactive attention and virtual long-term dependency modules, to capture the 3D interactions of all molecules. Through comprehensive evaluations across various tasks such as protein design, RNA design, and material design, we demonstrate that our proposed method surpasses state-of-the-art methods on all tasks. UniIF offers a versatile and effective solution for general molecule inverse folding.

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ICML Conference 2024 Conference Paper

VQDNA: Unleashing the Power of Vector Quantization for Multi-Species Genomic Sequence Modeling

  • Siyuan Li 0002
  • Zedong Wang
  • Zicheng Liu 0006
  • Di Wu 0057
  • Cheng Tan 0012
  • Jiangbin Zheng 0002
  • Yufei Huang 0002
  • Stan Z. Li

Similar to natural language models, pre-trained genome language models are proposed to capture the underlying intricacies within genomes with unsupervised sequence modeling. They have become essential tools for researchers and practitioners in biology. However, the hand-crafted tokenization policies used in these models may not encode the most discriminative patterns from the limited vocabulary of genomic data. In this paper, we introduce VQDNA, a general-purpose framework that renovates genome tokenization from the perspective of genome vocabulary learning. By leveraging vector-quantized codebook as learnable vocabulary, VQDNA can adaptively tokenize genomes into pattern-aware embeddings in an end-to-end manner. To further push its limits, we propose Hierarchical Residual Quantization (HRQ), where varying scales of codebooks are designed in a hierarchy to enrich the genome vocabulary in a coarse-to-fine manner. Extensive experiments on 32 genome datasets demonstrate VQDNA’s superiority and favorable parameter efficiency compared to existing genome language models. Notably, empirical analysis of SARS-CoV-2 mutations reveals the fine-grained pattern awareness and biological significance of learned HRQ vocabulary, highlighting its untapped potential for broader applications in genomics.

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AAAI Conference 2024 Conference Paper

Wavelet-Driven Spatiotemporal Predictive Learning: Bridging Frequency and Time Variations

  • Xuesong Nie
  • Yunfeng Yan
  • Siyuan Li
  • Cheng Tan
  • Xi Chen
  • Haoyuan Jin
  • Zhihang Zhu
  • Stan Z. Li

Spatiotemporal predictive learning is a paradigm that empowers models to learn spatial and temporal patterns by predicting future frames from past frames in an unsupervised manner. This method typically uses recurrent units to capture long-term dependencies, but these units often come with high computational costs and limited performance in real-world scenes. This paper presents an innovative Wavelet-based SpatioTemporal (WaST) framework, which extracts and adaptively controls both low and high-frequency components at image and feature levels via 3D discrete wavelet transform for faster processing while maintaining high-quality predictions. We propose a Time-Frequency Aware Translator uniquely crafted to efficiently learn short- and long-range spatiotemporal information by individually modeling spatial frequency and temporal variations. Meanwhile, we design a wavelet-domain High-Frequency Focal Loss that effectively supervises high-frequency variations. Extensive experiments across various real-world scenarios, such as driving scene prediction, traffic flow prediction, human motion capture, and weather forecasting, demonstrate that our proposed WaST achieves state-of-the-art performance over various spatiotemporal prediction methods.

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NeurIPS Conference 2023 Conference Paper

A Hierarchical Training Paradigm for Antibody Structure-sequence Co-design

  • Fang Wu
  • Stan Z. Li

Therapeutic antibodies are an essential and rapidly flourishing drug modality. The binding specificity between antibodies and antigens is decided by complementarity-determining regions (CDRs) at the tips of these Y-shaped proteins. In this paper, we propose a \textbf{h}ierarchical \textbf{t}raining \textbf{p}aradigm (HTP) for the antibody sequence-structure co-design. HTP consists of four levels of training stages, each corresponding to a specific protein modality within a particular protein domain. Through carefully crafted tasks in different stages, HTP seamlessly and effectively integrates geometric graph neural networks (GNNs) with large-scale protein language models to excavate evolutionary information from not only geometric structures but also vast antibody and non-antibody sequence databases, which determines ligand binding pose and strength. Empirical experiments show HTP sets the new state-of-the-art performance in the co-design problem as well as the fix-backbone design. Our research offers a hopeful path to unleash the potential of deep generative architectures and seeks to illuminate the way forward for the antibody sequence and structure co-design challenge.

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IJCAI Conference 2023 Conference Paper

A Systematic Survey of Chemical Pre-trained Models

  • Jun Xia
  • Yanqiao Zhu
  • Yuanqi Du
  • Stan Z. Li

Deep learning has achieved remarkable success in learning representations for molecules, which is crucial for various biochemical applications, ranging from property prediction to drug design. However, training Deep Neural Networks (DNNs) from scratch often requires abundant labeled molecules, which are expensive to acquire in the real world. To alleviate this issue, tremendous efforts have been devoted to Chemical Pre-trained Models (CPMs), where DNNs are pre-trained using large-scale unlabeled molecular databases and then fine-tuned over specific downstream tasks. Despite the prosperity, there lacks a systematic review of this fast-growing field. In this paper, we present the first survey that summarizes the current progress of CPMs. We first highlight the limitations of training molecular representation models from scratch to motivate CPM studies. Next, we systematically review recent advances on this topic from several key perspectives, including molecular descriptors, encoder architectures, pre-training strategies, and applications. We also highlight the challenges and promising avenues for future research, providing a useful resource for both machine learning and scientific communities.

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ICML Conference 2023 Conference Paper

Architecture-Agnostic Masked Image Modeling - From ViT back to CNN

  • Siyuan Li 0002
  • Di Wu 0057
  • Fang Wu 0002
  • Zelin Zang
  • Stan Z. Li

Masked image modeling, an emerging self-supervised pre-training method, has shown impressive success across numerous downstream vision tasks with Vision transformers. Its underlying idea is simple: a portion of the input image is masked out and then reconstructed via a pre-text task. However, the working principle behind MIM is not well explained, and previous studies insist that MIM primarily works for the Transformer family but is incompatible with CNNs. In this work, we observe that MIM essentially teaches the model to learn better middle-order interactions among patches for more generalized feature extraction. We then propose an Architecture-Agnostic Masked Image Modeling framework (A$^2$MIM), which is compatible with both Transformers and CNNs in a unified way. Extensive experiments on popular benchmarks show that A$^2$MIM learns better representations without explicit design and endows the backbone model with the stronger capability to transfer to various downstream tasks.

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AAAI Conference 2023 Conference Paper

DiffMD: A Geometric Diffusion Model for Molecular Dynamics Simulations

  • Fang Wu
  • Stan Z. Li

Molecular dynamics (MD) has long been the de facto choice for simulating complex atomistic systems from first principles. Recently deep learning models become a popular way to accelerate MD. Notwithstanding, existing models depend on intermediate variables such as the potential energy or force fields to update atomic positions, which requires additional computations to perform back-propagation. To waive this requirement, we propose a novel model called DiffMD by directly estimating the gradient of the log density of molecular conformations. DiffMD relies on a score-based denoising diffusion generative model that perturbs the molecular structure with a conditional noise depending on atomic accelerations and treats conformations at previous timeframes as the prior distribution for sampling. Another challenge of modeling such a conformation generation process is that a molecule is kinetic instead of static, which no prior works have strictly studied. To solve this challenge, we propose an equivariant geometric Transformer as the score function in the diffusion process to calculate corresponding gradients. It incorporates the directions and velocities of atomic motions via 3D spherical Fourier-Bessel representations. With multiple architectural improvements, we outperform state-of-the-art baselines on MD17 and isomers of C7O2H10 datasets. This work contributes to accelerating material and drug discovery.

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ICML Conference 2023 Conference Paper

Dink-Net: Neural Clustering on Large Graphs

  • Yue Liu 0008
  • Ke Liang 0006
  • Jun Xia 0001
  • Sihang Zhou 0001
  • Xihong Yang
  • Xinwang Liu 0002
  • Stan Z. Li

Deep graph clustering, which aims to group the nodes of a graph into disjoint clusters with deep neural networks, has achieved promising progress in recent years. However, the existing methods fail to scale to the large graph with million nodes. To solve this problem, a scalable deep graph clustering method (Dink-Net) is proposed with the idea of dilation and shrink. Firstly, by discriminating nodes, whether being corrupted by augmentations, representations are learned in a self-supervised manner. Meanwhile, the cluster centers are initialized as learnable neural parameters. Subsequently, the clustering distribution is optimized by minimizing the proposed cluster dilation loss and cluster shrink loss in an adversarial manner. By these settings, we unify the two-step clustering, i. e. , representation learning and clustering optimization, into an end-to-end framework, guiding the network to learn clustering-friendly features. Besides, Dink-Net scales well to large graphs since the designed loss functions adopt the mini-batch data to optimize the clustering distribution even without performance drops. Both experimental results and theoretical analyses demonstrate the superiority of our method. Compared to the runner-up, Dink-Net achieves $9. 62%$ NMI improvement on the ogbn-papers100M dataset with 111 million nodes and 1. 6 billion edges. The source code is released: https: //github. com/yueliu1999/Dink-Net. Besides, a collection (papers, codes, and datasets) of deep graph clustering is shared on GitHub https: //github. com/yueliu1999/Awesome-Deep-Graph-Clustering.

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AAAI Conference 2023 Conference Paper

Extracting Low-/High- Frequency Knowledge from Graph Neural Networks and Injecting It into MLPs: An Effective GNN-to-MLP Distillation Framework

  • Lirong Wu
  • Haitao Lin
  • Yufei Huang
  • Tianyu Fan
  • Stan Z. Li

Recent years have witnessed the great success of Graph Neural Networks (GNNs) in handling graph-related tasks. However, MLPs remain the primary workhorse for practical industrial applications due to their desirable inference efficiency and scalability. To reduce their gaps, one can directly distill knowledge from a well-designed teacher GNN to a student MLP, which is termed as GNN-to-MLP distillation. However, the process of distillation usually entails a loss of information, and ``which knowledge patterns of GNNs are more likely to be left and distilled into MLPs?" becomes an important question. In this paper, we first factorize the knowledge learned by GNNs into low- and high-frequency components in the spectral domain and then derive their correspondence in the spatial domain. Furthermore, we identified a potential information drowning problem for existing GNN-to-MLP distillation, i.e., the high-frequency knowledge of the pre-trained GNNs may be overwhelmed by the low-frequency knowledge during distillation; we have described in detail what it represents, how it arises, what impact it has, and how to deal with it. In this paper, we propose an efficient Full-Frequency GNN-to-MLP (FF-G2M) distillation framework, which extracts both low-frequency and high-frequency knowledge from GNNs and injects it into MLPs. Extensive experiments show that FF-G2M improves over the vanilla MLPs by 12.6% and outperforms its corresponding teacher GNNs by 2.6% averaged over six graph datasets and three common GNN architectures.

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NeurIPS Conference 2023 Conference Paper

Functional-Group-Based Diffusion for Pocket-Specific Molecule Generation and Elaboration

  • Haitao Lin
  • Yufei Huang
  • Odin Zhang
  • Yunfan Liu
  • Lirong Wu
  • Siyuan Li
  • Zhiyuan Chen
  • Stan Z. Li

In recent years, AI-assisted drug design methods have been proposed to generate molecules given the pockets' structures of target proteins. Most of them are {\em atom-level-based} methods, which consider atoms as basic components and generate atom positions and types. In this way, however, it is hard to generate realistic fragments with complicated structures. To solve this, we propose \textsc{D3FG}, a {\em functional-group-based} diffusion model for pocket-specific molecule generation and elaboration. \textsc{D3FG} decomposes molecules into two categories of components: functional groups defined as rigid bodies and linkers as mass points. And the two kinds of components can together form complicated fragments that enhance ligand-protein interactions. To be specific, in the diffusion process, \textsc{D3FG} diffuses the data distribution of the positions, orientations, and types of the components into a prior distribution; In the generative process, the noise is gradually removed from the three variables by denoisers parameterized with designed equivariant graph neural networks. In the experiments, our method can generate molecules with more realistic 3D structures, competitive affinities toward the protein targets, and better drug properties. Besides, \textsc{D3FG} as a solution to a new task of molecule elaboration, could generate molecules with high affinities based on existing ligands and the hotspots of target proteins.

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NeurIPS Conference 2023 Conference Paper

Harnessing Hard Mixed Samples with Decoupled Regularizer

  • Zicheng Liu
  • Siyuan Li
  • Ge Wang
  • Lirong Wu
  • Cheng Tan
  • Stan Z. Li

Mixup is an efficient data augmentation approach that improves the generalization of neural networks by smoothing the decision boundary with mixed data. Recently, dynamic mixup methods have improved previous \textit{static} policies effectively (e. g. , linear interpolation) by maximizing target-related salient regions in mixed samples, but excessive additional time costs are not acceptable. These additional computational overheads mainly come from optimizing the mixed samples according to the mixed labels. However, we found that the extra optimizing step may be redundant because label-mismatched mixed samples are informative hard mixed samples for deep models to localize discriminative features. In this paper, we thus are not trying to propose a more complicated dynamic mixup policy but rather an efficient mixup objective function with decoupled regularizer, named decoupled mixup (DM). The primary effect is that DM can adaptively utilize those hard mixed samples to mine discriminative features without losing the original smoothness of mixup. As a result, DM enables static mixup methods to achieve comparable or even exceed the performance of dynamic methods without any extra computation. This also leads to an interesting objective design problem for mixup training that we need to focus on both smoothing the decision boundaries and identifying discriminative features. Extensive experiments on supervised and semi-supervised learning benchmarks across seven datasets validate the effectiveness of DM.

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ICML Conference 2023 Conference Paper

High-dimensional Clustering onto Hamiltonian Cycle

  • Tianyi Huang
  • Shenghui Cheng
  • Stan Z. Li
  • Zhengjun Zhang

Clustering aims to group unlabelled samples based on their similarities and is widespread in high-dimensional data analysis. However, most of the clustering methods merely generate pseudo labels and thus are unable to simultaneously present the similarities between different clusters and outliers. This paper proposes a new framework called High-dimensional Clustering onto Hamiltonian Cycle (HCHC) to solve the above problems. First, HCHC combines global structure with local structure in one objective function for deep clustering, improving the labels as relative probabilities, to mine the similarities between different clusters while keeping the local structure in each cluster. Then, the anchors of different clusters are sorted on the optimal Hamiltonian cycle generated by the cluster similarities and mapped on the circumference of a circle. Finally, a sample with a higher probability of a cluster will be mapped closer to the corresponding anchor. In this way, our framework allows us to appreciate three aspects visually and simultaneously - clusters (formed by samples with high probabilities), cluster similarities (represented as circular distances), and outliers (recognized as dots far away from all clusters). The theoretical analysis and experiments illustrate the superiority of HCHC.

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ICLR Conference 2023 Conference Paper

Mole-BERT: Rethinking Pre-training Graph Neural Networks for Molecules

  • Jun Xia 0001
  • Chengshuai Zhao
  • Bozhen Hu
  • Zhangyang Gao
  • Cheng Tan 0012
  • Yue Liu 0008
  • Siyuan Li 0002
  • Stan Z. Li

Recent years have witnessed the prosperity of pre-training graph neural networks (GNNs) for molecules. Typically, atom types as node attributes are randomly masked, and GNNs are then trained to predict masked types as in AttrMask \citep{hu2020strategies}, following the Masked Language Modeling (MLM) task of BERT~\citep{devlin2019bert}. However, unlike MLM with a large vocabulary, the AttrMask pre-training does not learn informative molecular representations due to small and unbalanced atom `vocabulary'. To amend this problem, we propose a variant of VQ-VAE~\citep{van2017neural} as a context-aware tokenizer to encode atom attributes into chemically meaningful discrete codes. This can enlarge the atom vocabulary size and mitigate the quantitative divergence between dominant (e.g., carbons) and rare atoms (e.g., phosphorus). With the enlarged atom `vocabulary', we propose a novel node-level pre-training task, dubbed Masked Atoms Modeling (\textbf{MAM}), to mask some discrete codes randomly and then pre-train GNNs to predict them. MAM also mitigates another issue of AttrMask, namely the negative transfer. It can be easily combined with various pre-training tasks to improve their performance. Furthermore, we propose triplet masked contrastive learning (\textbf{TMCL}) for graph-level pre-training to model the heterogeneous semantic similarity between molecules for effective molecule retrieval. MAM and TMCL constitute a novel pre-training framework, \textbf{Mole-BERT}, which can match or outperform state-of-the-art methods in a fully data-driven manner. We release the code at \textcolor{magenta}{\url{https://github.com/junxia97/Mole-BERT}}.

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AAAI Conference 2023 Conference Paper

Molformer: Motif-Based Transformer on 3D Heterogeneous Molecular Graphs

  • Fang Wu
  • Dragomir Radev
  • Stan Z. Li

Procuring expressive molecular representations underpins AI-driven molecule design and scientific discovery. The research mainly focuses on atom-level homogeneous molecular graphs, ignoring the rich information in subgraphs or motifs. However, it has been widely accepted that substructures play a dominant role in identifying and determining molecular properties. To address such issues, we formulate heterogeneous molecular graphs (HMGs) and introduce a novel architecture to exploit both molecular motifs and 3D geometry. Precisely, we extract functional groups as motifs for small molecules and employ reinforcement learning to adaptively select quaternary amino acids as motif candidates for proteins. Then HMGs are constructed with both atom-level and motif-level nodes. To better accommodate those HMGs, we introduce a variant of the Transformer named Molformer, which adopts a heterogeneous self-attention layer to distinguish the interactions between multi-level nodes. Besides, it is also coupled with a multi-scale mechanism to capture fine-grained local patterns with increasing contextual scales. An attentive farthest point sampling algorithm is also proposed to obtain the molecular representations. We validate Molformer across a broad range of domains, including quantum chemistry, physiology, and biophysics. Extensive experiments show that Molformer outperforms or achieves the comparable performance of several state-of-the-art baselines. Our work provides a promising way to utilize informative motifs from the perspective of multi-level graph construction. The code is available at https://github.com/smiles724/Molformer.

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NeurIPS Conference 2023 Conference Paper

OpenSTL: A Comprehensive Benchmark of Spatio-Temporal Predictive Learning

  • Cheng Tan
  • Siyuan Li
  • Zhangyang Gao
  • Wenfei Guan
  • Zedong Wang
  • Zicheng Liu
  • Lirong Wu
  • Stan Z. Li

Spatio-temporal predictive learning is a learning paradigm that enables models to learn spatial and temporal patterns by predicting future frames from given past frames in an unsupervised manner. Despite remarkable progress in recent years, a lack of systematic understanding persists due to the diverse settings, complex implementation, and difficult reproducibility. Without standardization, comparisons can be unfair and insights inconclusive. To address this dilemma, we propose OpenSTL, a comprehensive benchmark for spatio-temporal predictive learning that categorizes prevalent approaches into recurrent-based and recurrent-free models. OpenSTL provides a modular and extensible framework implementing various state-of-the-art methods. We conduct standard evaluations on datasets across various domains, including synthetic moving object trajectory, human motion, driving scenes, traffic flow, and weather forecasting. Based on our observations, we provide a detailed analysis of how model architecture and dataset properties affect spatio-temporal predictive learning performance. Surprisingly, we find that recurrent-free models achieve a good balance between efficiency and performance than recurrent models. Thus, we further extend the common MetaFormers to boost recurrent-free spatial-temporal predictive learning. We open-source the code and models at https: //github. com/chengtan9907/OpenSTL.

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ICLR Conference 2023 Conference Paper

PiFold: Toward effective and efficient protein inverse folding

  • Zhangyang Gao
  • Cheng Tan 0012
  • Stan Z. Li

How can we design protein sequences folding into the desired structures effectively and efficiently? AI methods for structure-based protein design have attracted increasing attention in recent years; however, few methods can simultaneously improve the accuracy and efficiency due to the lack of expressive features and autoregressive sequence decoder. To address these issues, we propose PiFold, which contains a novel residue featurizer and PiGNN layers to generate protein sequences in a one-shot way with improved recovery. Experiments show that PiFold could achieve 51.66\% recovery on CATH 4.2, while the inference speed is 70 times faster than the autoregressive competitors. In addition, PiFold achieves 58.72\% and 60.42\% recovery scores on TS50 and TS500, respectively. We conduct comprehensive ablation studies to reveal the role of different types of protein features and model designs, inspiring further simplification and improvement. The PyTorch code is available at \href{https://github.com/A4Bio/PiFold}{GitHub}.

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NeurIPS Conference 2023 Conference Paper

ProteinInvBench: Benchmarking Protein Inverse Folding on Diverse Tasks, Models, and Metrics

  • Zhangyang Gao
  • Cheng Tan
  • Yijie Zhang
  • Xingran Chen
  • Lirong Wu
  • Stan Z. Li

Protein inverse folding has attracted increasing attention in recent years. However, we observe that current methods are usually limited to the CATH dataset and the recovery metric. The lack of a unified framework for ensembling and comparing different methods hinders the comprehensive investigation. In this paper, we propose ProteinBench, a new benchmark for protein design, which comprises extended protein design tasks, integrated models, and diverse evaluation metrics. We broaden the application of methods originally designed for single-chain protein design to new scenarios of multi-chain and \textit{de novo} protein design. Recent impressive methods, including GraphTrans, StructGNN, GVP, GCA, AlphaDesign, ProteinMPNN, PiFold and KWDesign are integrated into our framework. In addition to the recovery, we also evaluate the confidence, diversity, sc-TM, efficiency, and robustness to thoroughly revisit current protein design approaches and inspire future work. As a result, we establish the first comprehensive benchmark for protein design, which is publicly available at \url{https: //github. com/A4Bio/OpenCPD}.

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ICML Conference 2023 Conference Paper

Quantifying the Knowledge in GNNs for Reliable Distillation into MLPs

  • Lirong Wu
  • Haitao Lin
  • Yufei Huang 0002
  • Stan Z. Li

To bridge the gaps between topology-aware Graph Neural Networks (GNNs) and inference-efficient Multi-Layer Perceptron (MLPs), GLNN proposes to distill knowledge from a well-trained teacher GNN into a student MLP. Despite their great progress, comparatively little work has been done to explore the reliability of different knowledge points (nodes) in GNNs, especially their roles played during distillation. In this paper, we first quantify the knowledge reliability in GNN by measuring the invariance of their information entropy to noise perturbations, from which we observe that different knowledge points (1) show different distillation speeds (temporally); (2) are differentially distributed in the graph (spatially). To achieve reliable distillation, we propose an effective approach, namely Knowledge-inspired Reliable Distillation (KRD), that models the probability of each node being an informative and reliable knowledge point, based on which we sample a set of additional reliable knowledge points as supervision for training student MLPs. Extensive experiments show that KRD improves over the vanilla MLPs by 12. 62% and outperforms its corresponding teacher GNNs by 2. 16% averaged over 7 datasets and 3 GNN architectures. Codes are publicly available at: https: //github. com/LirongWu/RKD.

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ICML Conference 2023 Conference Paper

Rethinking Explaining Graph Neural Networks via Non-parametric Subgraph Matching

  • Fang Wu 0002
  • Siyuan Li 0002
  • Xurui Jin
  • Yinghui Jiang
  • Dragomir Radev
  • Zhangming Niu
  • Stan Z. Li

The success of graph neural networks (GNNs) provokes the question about explainability: “Which fraction of the input graph is the most determinant of the prediction? ” Particularly, parametric explainers prevail in existing approaches because of their more robust capability to decipher the black-box (i. e. , target GNNs). In this paper, based on the observation that graphs typically share some common motif patterns, we propose a novel non-parametric subgraph matching framework, dubbed MatchExplainer, to explore explanatory subgraphs. It couples the target graph with other counterpart instances and identifies the most crucial joint substructure by minimizing the node corresponding-based distance. Moreover, we note that present graph sampling or node-dropping methods usually suffer from the false positive sampling problem. To alleviate this issue, we design a new augmentation paradigm named MatchDrop. It takes advantage of MatchExplainer to fix the most informative portion of the graph and merely operates graph augmentations on the rest less informative part. Extensive experiments on synthetic and real-world datasets show the effectiveness of our MatchExplainer by outperforming all state-of-the-art parametric baselines with significant margins. Results also demonstrate that MatchDrop is a general scheme to be equipped with GNNs for enhanced performance. The code is available at https: //github. com/smiles724/MatchExplainer.

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NeurIPS Conference 2023 Conference Paper

Understanding the Limitations of Deep Models for Molecular property prediction: Insights and Solutions

  • Jun Xia
  • Lecheng Zhang
  • Xiao Zhu
  • Yue Liu
  • Zhangyang Gao
  • Bozhen Hu
  • Cheng Tan
  • Jiangbin Zheng

Molecular Property Prediction (MPP) is a crucial task in the AI-driven Drug Discovery (AIDD) pipeline, which has recently gained considerable attention thanks to advancements in deep learning. However, recent research has revealed that deep models struggle to beat traditional non-deep ones on MPP. In this study, we benchmark 12 representative models (3 non-deep models and 9 deep models) on 15 molecule datasets. Through the most comprehensive study to date, we make the following key observations: \textbf{(\romannumeral 1)} Deep models are generally unable to outperform non-deep ones; \textbf{(\romannumeral 2)} The failure of deep models on MPP cannot be solely attributed to the small size of molecular datasets; \textbf{(\romannumeral 3)} In particular, some traditional models including XGB and RF that use molecular fingerprints as inputs tend to perform better than other competitors. Furthermore, we conduct extensive empirical investigations into the unique patterns of molecule data and inductive biases of various models underlying these phenomena. These findings stimulate us to develop a simple-yet-effective feature mapping method for molecule data prior to feeding them into deep models. Empirically, deep models equipped with this mapping method can beat non-deep ones in most MoleculeNet datasets. Notably, the effectiveness is further corroborated by extensive experiments on cutting-edge dataset related to COVID-19 and activity cliff datasets.

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AAAI Conference 2022 Conference Paper

Conditional Local Convolution for Spatio-Temporal Meteorological Forecasting

  • Haitao Lin
  • Zhangyang Gao
  • Yongjie Xu
  • Lirong Wu
  • Ling Li
  • Stan Z. Li

Spatio-temporal forecasting is challenging attributing to the high nonlinearity in temporal dynamics as well as complex location-characterized patterns in spatial domains, especially in fields like weather forecasting. Graph convolutions are usually used for modeling the spatial dependency in meteorology to handle the irregular distribution of sensors' spatial location. In this work, a novel graph-based convolution for imitating the meteorological flows is proposed to capture the local spatial patterns. Based on the assumption of smoothness of location-characterized patterns, we propose conditional local convolution whose shared kernel on nodes' local space is approximated by feedforward networks, with local representations of coordinate obtained by horizon maps into cylindrical-tangent space as its input. The established united standard of local coordinate system preserves the orientation on geography. We further propose the distance and orientation scaling terms to reduce the impacts of irregular spatial distribution. The convolution is embedded in a Recurrent Neural Network architecture to model the temporal dynamics, leading to the Conditional Local Convolution Recurrent Network (CLCRN). Our model is evaluated on real-world weather benchmark datasets, achieving state-of-the-art performance with obvious improvements. We conduct further analysis on local pattern visualization, model's framework choice, advantages of horizon maps and etc. The source code is available at https://github.com/BIRD-TAO/CLCRN.

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TMLR Journal 2022 Journal Article

Exploring Generative Neural Temporal Point Process

  • Haitao Lin
  • Lirong Wu
  • Guojiang Zhao
  • Liu Pai
  • Stan Z. Li

Temporal point process (TPP) is commonly used to model the asynchronous event sequence featuring occurrence timestamps and revealed by probabilistic models conditioned on historical impacts. While lots of previous works have focused on `goodness-of-fit' of TPP models by maximizing the likelihood, their predictive performance is unsatisfactory, which means the timestamps generated by models are far apart from true observations. Recently, deep generative models such as denoising diffusion and score matching models have achieved great progress in image generating tasks by demonstrating their capability of generating samples of high quality. However, there are no detailed and unified works exploring and studying the potential of generative models in the context of event prediction of TPP. In this work, we try to fill the gap by designing a unified generative framework for neural temporal point process (GNTPP) model to explore their feasibility and effectiveness, and further improve models' predictive performance. Besides, in terms of measuring the historical impacts, we revise the attentive models which summarize influence from historical events with an adaptive reweighting term considering events' type relation and time intervals. Extensive experiments have been conducted to illustrate the improved predictive capability of GNTPP with a line of generative probabilistic decoders, and performance gain from the revised attention. To the best of our knowledge, this is the first work that adapts generative models in a complete unified framework and studies their effectiveness in the context of TPP.

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NeurIPS Conference 2022 Conference Paper

Knowledge Distillation Improves Graph Structure Augmentation for Graph Neural Networks

  • Lirong Wu
  • Haitao Lin
  • Yufei Huang
  • Stan Z. Li

Graph (structure) augmentation aims to perturb the graph structure through heuristic or probabilistic rules, enabling the nodes to capture richer contextual information and thus improving generalization performance. While there have been a few graph structure augmentation methods proposed recently, none of them are aware of a potential negative augmentation problem, which may be caused by overly severe distribution shifts between the original and augmented graphs. In this paper, we take an important graph property, namely graph homophily, to analyze the distribution shifts between the two graphs and thus measure the severity of an augmentation algorithm suffering from negative augmentation. To tackle this problem, we propose a novel Knowledge Distillation for Graph Augmentation (KDGA) framework, which helps to reduce the potential negative effects of distribution shifts, i. e. , negative augmentation problem. Specifically, KDGA extracts the knowledge of any GNN teacher model trained on the augmented graphs and injects it into a partially parameter-shared student model that is tested on the original graph. As a simple but efficient framework, KDGA is applicable to a variety of existing graph augmentation methods and can significantly improve the performance of various GNN architectures. For three popular graph augmentation methods, namely GAUG, MH-Aug, and GraphAug, the experimental results show that the learned student models outperform their vanilla implementations by an average accuracy of 4. 6% (GAUG), 4. 2% (MH-Aug), and 4. 6% (GraphAug) on eight graph datasets.

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ICML Conference 2022 Conference Paper

ProGCL: Rethinking Hard Negative Mining in Graph Contrastive Learning

  • Jun Xia 0001
  • Lirong Wu
  • Ge Wang
  • Jintao Chen 0001
  • Stan Z. Li

Contrastive Learning (CL) has emerged as a dominant technique for unsupervised representation learning which embeds augmented versions of the anchor close to each other (positive samples) and pushes the embeddings of other samples (negatives) apart. As revealed in recent studies, CL can benefit from hard negatives (negatives that are most similar to the anchor). However, we observe limited benefits when we adopt existing hard negative mining techniques of other domains in Graph Contrastive Learning (GCL). We perform both experimental and theoretical analysis on this phenomenon and find it can be attributed to the message passing of Graph Neural Networks (GNNs). Unlike CL in other domains, most hard negatives are potentially false negatives (negatives that share the same class with the anchor) if they are selected merely according to the similarities between anchor and themselves, which will undesirably push away the samples of the same class. To remedy this deficiency, we propose an effective method, dubbed \textbf{ProGCL}, to estimate the probability of a negative being true one, which constitutes a more suitable measure for negatives’ hardness together with similarity. Additionally, we devise two schemes (i. e. , \textbf{ProGCL-weight} and \textbf{ProGCL-mix}) to boost the performance of GCL. Extensive experiments demonstrate that ProGCL brings notable and consistent improvements over base GCL methods and yields multiple state-of-the-art results on several unsupervised benchmarks or even exceeds the performance of supervised ones. Also, ProGCL is readily pluggable into various negatives-based GCL methods for performance improvement. We release the code at \textcolor{magenta}\url{https: //github. com/junxia97/ProGCL}.

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NeurIPS Conference 2022 Conference Paper

Towards Reasonable Budget Allocation in Untargeted Graph Structure Attacks via Gradient Debias

  • Zihan Liu
  • Yun Luo
  • Lirong Wu
  • Zicheng Liu
  • Stan Z. Li

It has become cognitive inertia to employ cross-entropy loss function in classification related tasks. In the untargeted attacks on graph structure, the gradients derived from the attack objective are the attacker's basis for evaluating a perturbation scheme. Previous methods use negative cross-entropy loss as the attack objective in attacking node-level classification models. However, the suitability of the cross-entropy function for constructing the untargeted attack objective has yet been discussed in previous works. This paper argues about the previous unreasonable attack objective from the perspective of budget allocation. We demonstrate theoretically and empirically that negative cross-entropy tends to produce more significant gradients from nodes with lower confidence in the labeled classes, even if the predicted classes of these nodes have been misled. To free up these inefficient attack budgets, we propose a simple attack model for untargeted attacks on graph structure based on a novel attack objective which generates unweighted gradients on graph structures that are not affected by the node confidence. By conducting experiments in gray-box poisoning attack scenarios, we demonstrate that a reasonable budget allocation can significantly improve the effectiveness of gradient-based edge perturbations without any extra hyper-parameter.

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AAAI Conference 2020 Conference Paper

PedHunter: Occlusion Robust Pedestrian Detector in Crowded Scenes

  • Cheng Chi
  • Shifeng Zhang
  • Junliang Xing
  • Zhen Lei
  • Stan Z. Li
  • Xudong Zou

Pedestrian detection in crowded scenes is a challenging problem, because occlusion happens frequently among different pedestrians. In this paper, we propose an effective and efficient detection network to hunt pedestrians in crowd scenes. The proposed method, namely PedHunter, introduces strong occlusion handling ability to existing region-based detection networks without bringing extra computations in the inference stage. Specifically, we design a mask-guided module to leverage the head information to enhance the feature representation learning of the backbone network. Moreover, we develop a strict classification criterion by improving the quality of positive samples during training to eliminate common false positives of pedestrian detection in crowded scenes. Besides, we present an occlusion-simulated data augmentation to enrich the pattern and quantity of occlusion samples to improve the occlusion robustness. As a consequent, we achieve state-of-the-art results on three pedestrian detection datasets including CityPersons, Caltech-USA and CrowdHuman. To facilitate further studies on the occluded pedestrian detection in surveillance scenes, we release a new pedestrian dataset, called SUR-PED, with a total of over 162k highquality manually labeled instances in 10k images. The proposed dataset, source codes and trained models are available at https: //github. com/ChiCheng123/PedHunter.

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AAAI Conference 2020 Conference Paper

Relation-Aware Pedestrian Attribute Recognition with Graph Convolutional Networks

  • Zichang Tan
  • Yang Yang
  • Jun Wan
  • Guodong Guo
  • Stan Z. Li

In this paper, we propose a new end-to-end network, named Joint Learning of Attribute and Contextual relations (JLAC), to solve the task of pedestrian attribute recognition. It includes two novel modules: Attribute Relation Module (ARM) and Contextual Relation Module (CRM). For ARM, we construct an attribute graph with attribute-specific features which are learned by the constrained losses, and further use Graph Convolutional Network (GCN) to explore the correlations among multiple attributes. For CRM, we first propose a graph projection scheme to project the 2-D feature map into a set of nodes from different image regions, and then employ GCN to explore the contextual relations among those regions. Since the relation information in the above two modules is correlated and complementary, we incorporate them into a unified framework to learn both together. Experiments on three benchmarks, including PA-100K, RAP, PETA attribute datasets, demonstrate the effectiveness of the proposed JLAC.

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AAAI Conference 2020 Conference Paper

Relational Learning for Joint Head and Human Detection

  • Cheng Chi
  • Shifeng Zhang
  • Junliang Xing
  • Zhen Lei
  • Stan Z. Li
  • Xudong Zou

Head and human detection have been rapidly improved with the development of deep convolutional neural networks. However, these two tasks are often studied separately without considering their inherent correlation, leading to that 1) head detection is often trapped in more false positives, and 2) the performance of human detector frequently drops dramatically in crowd scenes. To handle these two issues, we present a novel joint head and human detection network, namely JointDet, which effectively detects head and human body simultaneously. Moreover, we design a head-body relationship discriminating module to perform relational learning between heads and human bodies, and leverage this learned relationship to regain the suppressed human detections and reduce head false positives. To verify the effectiveness of the proposed method, we annotate head bounding boxes of the CityPersons and Caltech-USA datasets, and conduct extensive experiments on the CrowdHuman, CityPersons and Caltech-USA datasets. As a consequence, the proposed Joint- Det detector achieves state-of-the-art performance on these three benchmarks. To facilitate further studies on the head and human detection problem, all new annotations, source codes and trained models are available at https: //github. com/ ChiCheng123/JointDet.

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IJCAI Conference 2019 Conference Paper

Deeply-learned Hybrid Representations for Facial Age Estimation

  • Zichang Tan
  • Yang Yang
  • Jun Wan
  • Guodong Guo
  • Stan Z. Li

In this paper, we propose a novel unified network named Deep Hybrid-Aligned Architecture for facial age estimation. It contains global, local and global-local branches. They are jointly optimized and thus can capture multiple types of features with complementary information. In each branch, we employ a separate loss for each sub-network to extract the independent features and use a recurrent fusion to explore correlations among those region features. Considering that the pose variations may lead to misalignment in different regions, we design an Aligned Region Pooling operation to generate aligned region features. Moreover, a new large age dataset named Web-FaceAge owning more than 120K samples is collected under diverse scenes and spanning a large age range. Experiments on five age benchmark datasets, including Web-FaceAge, Morph, FG-NET, CACD and Chalearn LAP 2015, show that the proposed method outperforms the state-of-the-art approaches significantly.

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AAAI Conference 2019 Conference Paper

Selective Refinement Network for High Performance Face Detection

  • Cheng Chi
  • Shifeng Zhang
  • Junliang Xing
  • Zhen Lei
  • Stan Z. Li
  • Xudong Zou

High performance face detection remains a very challenging problem, especially when there exists many tiny faces. This paper presents a novel single-shot face detector, named Selective Refinement Network (SRN), which introduces novel twostep classification and regression operations selectively into an anchor-based face detector to reduce false positives and improve location accuracy simultaneously. In particular, the SRN consists of two modules: the Selective Two-step Classification (STC) module and the Selective Two-step Regression (STR) module. The STC aims to filter out most simple negative anchors from low level detection layers to reduce the search space for the subsequent classifier, while the STR is designed to coarsely adjust the locations and sizes of anchors from high level detection layers to provide better initialization for the subsequent regressor. Moreover, we design a Receptive Field Enhancement (RFE) block to provide more diverse receptive field, which helps to better capture faces in some extreme poses. As a consequence, the proposed SRN detector achieves state-of-the-art performance on all the widely used face detection benchmarks, including AFW, PASCAL face, FDDB, and WIDER FACE datasets. Codes will be released to facilitate further studies on the face detection problem.

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IJCAI Conference 2018 Conference Paper

Ensemble Soft-Margin Softmax Loss for Image Classification

  • Xiaobo Wang
  • Shifeng Zhang
  • Zhen Lei
  • Si Liu
  • Xiaojie Guo
  • Stan Z. Li

Softmax loss is arguably one of the most popular losses to train CNN models for image classification. However, recent works have exposed its limitation on feature discriminability. This paper casts a new viewpoint on the weakness of softmax loss. On the one hand, the CNN features learned using the softmax loss are often inadequately discriminative. We hence introduce a soft-margin softmax function to explicitly encourage the discrmination between different classes. On the other hand, the learned classifier of softmax loss is weak. We propose to assemble multiple these weak classifiers to a strong one, inspired by the recognition that the diversity among weak classifiers is critical to a good ensemble. To achieve the diversity, we adopt the Hilbert-Schmidt Independence Criterion (HSIC). Considering these two aspects in one framework, we design a novel loss, named as Ensemble Soft-Margin Softmax (EM-Softmax). Extensive experiments on benchmark datasets are conducted to show the superiority of our design over the baseline softmax loss and several state-of-the-art alternatives.

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IS Journal 2018 Journal Article

Trends and Controversies

  • Hugo Proenca
  • Mark Nixon
  • Michele Nappi
  • Esam Ghaleb
  • Gokhan Ozbulak
  • Hua Gao
  • Hazim Kemal Ekenel
  • Klemen Grm

Performing covert biometric recognition in surveillance environments has been regarded as a grand challenge, considering the adversity of the conditions where recognition should be carried out (e. g. , poor resolution, bad lighting, off-pose and partially occluded data). This special issue compiles a group of approaches to this problem.

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v2026.09.13