系统梳理蛋白质生成建模的表示、架构与评估标准,推动设计向功能驱动演进。
Generative Modeling in Protein Design: Neural Representations, Conditional Generation, and Evaluation Standards
- 按序列、几何、多模态构建蛋白质表示框架
- 整合等变扩散、流匹配等生成架构,支持条件生成
- 提出防数据泄漏、物理合理性、功能导向的评估规范
生成建模已成为蛋白质研究的核心范式,将机器学习从结构预测拓展至序列设计、主链生成、逆折叠及生物分子相互作用建模。然而,现有文献在表示方式、模型类型和任务设定上分散割裂,难以比较方法或确立统一评估标准。本综述系统梳理了生成式AI在蛋白质研究中的进展,围绕三方面展开:(i) 序列、几何与多模态编码的基础表示;(ii) 包括 $ m{SE}(3)$-等变扩散、流匹配及混合预测-生成系统的生成架构;(iii) 从结构预测到从头设计,以及蛋白质-配体和蛋白质-蛋白质相互作用的任务设置。除方法归类外,还比较了假设、条件机制与可控性,并提炼出强调防数据泄露划分、物理有效性验证与功能导向基准的评估实践。最后指出关键开放挑战:建模构象动态与内在无序区域、在保持效率的前提下扩展至大型复合物、建立应对双用途生物安全风险的稳健安全框架。通过融合架构进展与实用评估标准及负责任研发考量,本综述旨在加速从预测建模向可信赖的功能驱动蛋白工程转变。
原文摘要 · Abstract (English)
Generative modeling has become a central paradigm in protein research, extending machine learning beyond structure prediction toward sequence design, backbone generation, inverse folding, and biomolecular interaction modeling. However, the literature remains fragmented across representations, model classes, and task formulations, making it difficult to compare methods or identify appropriate evaluation standards. This survey provides a systematic synthesis of generative AI in protein research, organized around (i) foundational representations spanning sequence, geometric, and multimodal encodings; (ii) generative architectures including $\mathrm{SE}(3)$-equivariant diffusion, flow matching, and hybrid predictor-generator systems; and (iii) task settings from structure prediction and de novo design to protein-ligand and protein-protein interactions. Beyond cataloging methods, we compare assumptions, conditioning mechanisms, and controllability, and we synthesize evaluation best practices that emphasize leakage-aware splits, physical validity checks, and function-oriented benchmarks. We conclude with critical open challenges: modeling conformational dynamics and intrinsically disordered regions, scaling to large assemblies while maintaining efficiency, and developing robust safety frameworks for dual-use biosecurity risks. By unifying architectural advances with practical evaluation standards and responsible development considerations, this survey aims to accelerate the transition from predictive modeling to reliable, function-driven protein engineering.
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