arXiv:2506.08954q-bio.QMcs.LG2025-06ICML被引 8

用可微分方法一键找蛋白同源序列,又快又准预测蛋白功能。

Protriever: End-to-End Differentiable Protein Homology Search for Fitness Prediction

  • 把找同源序列和训练模型合在一起,全程可微分优化。
  • 在蛋白适应度预测上超越传统方法,速度提升100倍。
  • 不依赖特定结构,能灵活适配不同数据库和任务。

同源蛋白序列检索对蛋白功能预测、设计、结构建模和蛋白质互作等任务至关重要。传统流程分两步:先用多序列比对(MSA)找同源序列,再基于这些比对结果训练模型。但MSA检索计算开销大,对高度分歧序列或复杂插入/缺失模式处理困难,且与下游建模目标脱节。我们提出Protriever,一个端到端可微分框架,能在训练时同时学习相关同源序列的检索与目标任务的建模。应用于蛋白适应度预测时,Protriever性能优于依赖MSA检索的序列模型,且通过高效向量搜索实现两数量级加速。该方法架构和任务无关,可灵活适配不同检索策略与蛋白数据库,是比对中心方法的可扩展替代方案。

原文摘要 · Abstract (English)

Retrieving homologous protein sequences is essential for a broad range of protein modeling tasks such as fitness prediction, protein design, structure modeling, and protein-protein interactions. Traditional workflows have relied on a two-step process: first retrieving homologs via Multiple Sequence Alignments (MSA), then training models on one or more of these alignments. However, MSA-based retrieval is computationally expensive, struggles with highly divergent sequences or complex insertions & deletions patterns, and operates independently of the downstream modeling objective. We introduce Protriever, an end-to-end differentiable framework that learns to retrieve relevant homologs while simultaneously training for the target task. When applied to protein fitness prediction, Protriever achieves state-of-the-art performance compared to sequence-based models that rely on MSA-based homolog retrieval, while being two orders of magnitude faster through efficient vector search. Protriever is both architecture- and task-agnostic, and can flexibly adapt to different retrieval strategies and protein databases at inference time -- offering a scalable alternative to alignment-centric approaches.

蛋白预测可微分检索高效算法

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