Siyuan Li

Cheng Tan, Zhenxiao Cao, Zhangyang Gao et al.

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. The code and datasets are available at https://github.com/A4Bio/MeToken.

Haitao Lin, Guojiang Zhao, Odin Zhang et al.

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

Changxi Chi, Jun Xia, Yufei Huang et al.

Estimating single-cell responses across various perturbations facilitates the identification of key genes and enhances drug screening, significantly boosting experimental efficiency. However, single-cell sequencing is a destructive process, making it impossible to capture the same cell's phenotype before and after perturbation. Consequently, data collected under perturbed and unperturbed conditions are inherently unpaired. Existing methods either attempt to forcibly pair unpaired data using random sampling, or neglect the inherent relationship between unperturbed and perturbed cells during the modeling. In this work, we propose a framework based on Dual Diffusion Implicit Bridges (DDIB) to learn the mapping between different data distributions, effectively addressing the challenge of unpaired data. We further interpret this framework as a form of data augmentation. We integrate gene regulatory network (GRN) information to propagate perturbation signals in a biologically meaningful way, and further incorporate a masking mechanism to predict silent genes, improving the quality of generated profiles. Moreover, gene expression under the same perturbation often varies significantly across cells, frequently exhibiting a bimodal distribution that reflects intrinsic heterogeneity. To capture this, we introduce a more suitable evaluation metric. We propose Unlasting, dual conditional diffusion models that overcome the problem of unpaired single-cell perturbation data and strengthen the model's insight into perturbations under the guidance of the GRN, with a dedicated mask model designed to improve generation quality by predicting silent genes. In addition, we introduce a biologically grounded evaluation metric that better reflects the inherent heterogeneity in single-cell responses.

Cheng Tan, Zhenxiao Cao, Zhangyang Gao et al.

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.

Yongyan Wen, Siyuan Li, Rongchang Zuo et al.

Deep reinforcement learning (DRL) has achieved remarkable success in various research domains. However, its reliance on neural networks results in a lack of transparency, which limits its practical applications. To achieve explainability, decision trees have emerged as a popular and promising alternative to neural networks. Nonetheless, due to their limited expressiveness, traditional decision trees struggle with high-dimensional long-horizon continuous control tasks. In this paper, we proposes SkillTree, a novel framework that reduces complex continuous action spaces into discrete skill spaces. Our hierarchical approach integrates a differentiable decision tree within the high-level policy to generate skill embeddings, which subsequently guide the low-level policy in executing skills. By making skill decisions explainable, we achieve skill-level explainability, enhancing the understanding of the decision-making process in complex tasks. Experimental results demonstrate that our method achieves performance comparable to skill-based neural networks in complex robotic arm control domains. Furthermore, SkillTree offers explanations at the skill level, thereby increasing the transparency of the decision-making process.

Siyuan Li, Xi Lin, Yaju Liu et al.

Deep Reinforcement Learning (DRL) is regarded as a promising tool for optical network optimization. However, the flexibility and efficiency of current DRL-based solutions for optical network optimization require further improvement. Currently, generative models have showcased their significant performance advantages across various domains. In this paper, we introduce OpticGAI, the AI-generated policy design paradigm for optical networks. In detail, it is implemented as a novel DRL framework that utilizes generative models to learn the optimal policy network. Furthermore, we assess the performance of OpticGAI on two NP-hard optical network problems, Routing and Wavelength Assignment (RWA) and dynamic Routing, Modulation, and Spectrum Allocation (RMSA), to show the feasibility of the AI-generated policy paradigm. Simulation results have shown that OpticGAI achieves the highest reward and the lowest blocking rate of both RWA and RMSA problems. OpticGAI poses a promising direction for future research on generative AI-enhanced flexible optical network optimization.

Siyuan Li, Rongchang Zuo, Bofei Liu et al.

Unmanned Combat Aerial Vehicle (UCAV) Within-Visual-Range (WVR) engagement, referring to a fight between two or more UCAVs at close quarters, plays a decisive role on the aerial battlefields. With the development of artificial intelligence, WVR engagement progressively advances towards intelligent and autonomous modes. However, autonomous WVR engagement policy learning is hindered by challenges such as weak exploration capabilities, low learning efficiency, and unrealistic simulated environments. To overcome these challenges, we propose a novel imitative reinforcement learning framework, which efficiently leverages expert data while enabling autonomous exploration. The proposed framework not only enhances learning efficiency through expert imitation, but also ensures adaptability to dynamic environments via autonomous exploration with reinforcement learning. Therefore, the proposed framework can learn a successful policy of `pursuit-lock-launch' for UCAVs. To support data-driven learning, we establish an environment based on the Harfang3D sandbox. The extensive experiment results indicate that the proposed framework excels in this multistage task, and significantly outperforms state-of-the-art reinforcement learning and imitation learning methods. Thanks to the ability of imitating experts and autonomous exploration, our framework can quickly learn the critical knowledge in complex aerial combat tasks, achieving up to a 100% success rate and demonstrating excellent robustness.