新预训练框架让蛋白质生成更真实,兼顾结构刚性和动态变化。
Rigidity-Aware Geometric Pretraining for Protein Design and Conformational Ensembles
- 用刚性感知的双向流匹配学习蛋白质几何先验
- 设计能力提升43%,零样本支架构建成功率提高5.8%
- 适合需要高保真构象模拟的蛋白质设计研究者
生成模型近年来通过学习天然结构的统计规律推动了从头蛋白质设计。但现有方法存在三大局限:(1)无法同时学习蛋白质几何与设计任务,预训练可缓解此问题;(2)现有预训练多依赖局部非刚性原子表征,限制对全局几何的理解;(3)尚未有效建模蛋白质结构丰富的动态与构象信息。为此,我们提出RigidSSL(刚性感知自监督学习),一个在生成微调前优先学习几何的预训练框架。第一阶段(RigidSSL-Perturb)基于AlphaFold蛋白结构数据库中的43.2万条结构,通过模拟扰动学习几何先验;第二阶段(RigidSSL-MD)在1.3千条分子动力学轨迹上精炼表示,捕捉物理上真实的构象转变。两个阶段均采用双向刚性感知流匹配目标,联合优化平移与旋转动态以最大化构象间的互信息。实验表明,RigidSSL变体使设计能力最高提升43%,无条件生成中新颖性与多样性显著增强;此外,RigidSSL-Perturb在零样本基序支架构建中成功率提升5.8%,RigidSSL-MD在G蛋白偶联受体建模中生成更具生物物理合理性的构象集合。
原文摘要 · Abstract (English)
Generative models have recently advanced $\textit{de novo}$ protein design by learning the statistical regularities of natural structures. However, current approaches face three key limitations: (1) Existing methods cannot jointly learn protein geometry and design tasks, where pretraining can be a solution; (2) Current pretraining methods mostly rely on local, non-rigid atomic representations for property prediction downstream tasks, limiting global geometric understanding for protein generation tasks; and (3) Existing approaches have yet to effectively model the rich dynamic and conformational information of protein structures. To overcome these issues, we introduce $\textbf{RigidSSL}$ ($\textit{Rigidity-Aware Self-Supervised Learning}$), a geometric pretraining framework that front-loads geometry learning prior to generative finetuning. Phase I (RigidSSL-Perturb) learns geometric priors from 432K structures from the AlphaFold Protein Structure Database with simulated perturbations. Phase II (RigidSSL-MD) refines these representations on 1.3K molecular dynamics trajectories to capture physically realistic transitions. Underpinning both phases is a bi-directional, rigidity-aware flow matching objective that jointly optimizes translational and rotational dynamics to maximize mutual information between conformations. Empirically, RigidSSL variants improve designability by up to 43% while enhancing novelty and diversity in unconditional generation. Furthermore, RigidSSL-Perturb improves the success rate by 5.8% in zero-shot motif scaffolding and RigidSSL-MD captures more biophysically realistic conformational ensembles in G protein-coupled receptor modeling.
Thank you to arXiv for use of its open access interoperability. PaperDance 不是 arXiv 官方产品;中文卡片由大模型生成,请以原文为准。