arXiv:2502.15855q-bio.QMcs.AI2025-02

提出分层时序流模型,让肽段先快速定位再协同优化构象,提升结合亲和力。

THFlow: A Temporally Hierarchical Flow Matching Framework for 3D Peptide Design

  • 分阶段生成:先快速对齐位置,再联合优化旋转与扭转
  • 在4个靶点上生成肽段的结合亲和力提升12%-23%
  • 适合药物研发人员设计高稳定性、高亲和力的治疗性肽段

深度生成模型为从头设计3D肽段提供了新路径。现有方法通常同时建模肽段的位置、取向和构象分布,试图同步收敛到目标结合口袋。然而,在对接初期,肽段远离蛋白口袋且无相互作用场时,仅优化构象(如旋转、二面角)在物理上并无意义。我们将其定义为多模态时序不一致问题,并指出这是导致生成肽段结合亲和力低的关键原因。为此,我们提出THFlow——一种基于流匹配的多模态生成框架,显式建模肽段位置与构象之间的时序层次关系。该模型采用基于多项式的条件流,早期加速位置收敛;随后在相互作用场出现后,协调对齐旋转与二面角进行构象精修。此外,引入极性等相互作用相关特征,增强模型对肽-蛋白结合的理解。大量实验表明,THFlow在生成肽段的稳定性、结合亲和力和多样性方面均优于现有方法,为推进肽类药物开发提供了高效准确的解决方案。

原文摘要 · Abstract (English)

Deep generative models provide a promising approach to de novo 3D peptide design. Most of them jointly model the distributions of peptide's position, orientation, and conformation, attempting to simultaneously converge to the target pocket. However, in the early stage of docking, optimizing conformation-only modalities such as rotation and torsion can be physically meaningless, as the peptide is initialized far from the protein pocket and no interaction field is present. We define this problem as the multimodal temporal inconsistency problem and claim it is a key factor contributing to low binding affinity in generated peptides. To address this challenge, we propose THFlow, a novel flow matching-based multimodal generative model that explicitly models the temporal hierarchy between peptide position and conformation. It employs a polynomial based conditional flow to accelerate positional convergence early on, and later aligns it with rotation and torsion for coordinated conformation refinement under the emerging interaction field. Additionally, we incorporate interaction-related features, such as polarity, to further enhance the model's understanding of peptide-protein binding. Extensive experiments demonstrate that THFlow outperforms existing methods in generating peptides with superior stability, affinity, and diversity, offering an effective and accurate solution for advancing peptide-based therapeutic development.

3D肽设计生成模型流匹配药物研发

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