提出可生成任意长度蛋白的新框架,突破固定长度限制。
Variable-Length Generative Protein Design via Generalized Poisson Flow

- 基于非齐次广义泊松过程建模,学习长度生成率函数
- 在结构与序列设计中均实现最优分布拟合与长度恢复
- 适合需探索未知长度的蛋白设计任务,如新功能蛋白开发
生成可变长度蛋白在蛋白设计中至关重要,因最优长度常未知且与可设计性紧密相关。现有基于扩散或流的生成模型通常需预先指定蛋白长度,限制了对可行设计空间的探索。为此,本文提出广义泊松流(GPFlow),通过最小化负对数似然学习非齐次广义泊松过程的速率函数。我们建立了群体层面的联合多模态分布恢复保证,并推导出数据分布与生成分布间KL散度的上界。在结构与序列设计、基序支架构建及肽类共设计等任务中全面评估,涵盖欧几里得、类别与黎曼模态,充分验证其可变长度生成质量。在无条件设计中,GPFlow提升结构可设计性,序列设计分布拟合优于对应固定长度基线,且完美恢复长度分布;在条件基序支架构建中,16项结构设计任务中10项排名第一,显著更多独特成功案例,序列设计也表现更优;在肽类共设计中,即使无天然长度先验仍保持竞争力。
原文摘要 · Abstract (English)
The ability to generate variable-length proteins is crucial in protein design, where the optimal length is often unknown and tightly coupled to designability. Current diffusion- and flow-based generative models typically require the protein length to be specified before sampling, limiting their flexibility in exploring the feasible design space. To address this limitation, we introduce Generalized Poisson Flow (GPFlow), a variable-length generative framework that learns the rate function of an inhomogeneous generalized Poisson process by minimizing its negative log-likelihood. We establish population-level guarantees for recovering the joint multimodal distribution and derive an upper bound on the KL divergence between the data and generated distributions. We comprehensively evaluate GPFlow across structure and sequence design, motif scaffolding, and peptide co-design, spanning Euclidean, categorical, and Riemannian modalities to fully validate its variable-length generation quality. In unconditional design, GPFlow improves structural designability and achieves the best distributional fitness for sequence design compared to their corresponding fixed-length baselines, while perfectly recovering the length distribution. In conditional motif scaffolding, GPFlow ranks first on 10 of 16 structure-based design tasks with significantly more unique successes and also achieves more passed tasks in sequence-based design. In peptide co-design, GPFlow remains competitive even without access to a native-length oracle.
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