arXiv:2506.00925q-bio.BMcs.CV2025-06NeurIPS被引 10

用树搜索生成多样且结构一致的蛋白质序列,突破传统方法局限。

ProtInvTree: Deliberate Protein Inverse Folding with Reward-guided Tree Search

  • 通过奖励引导的树搜索,分步决策设计蛋白质序列。
  • 在多个基准上生成结构一致且差异显著的序列,超越现有方法。
  • 适合需要多样化蛋白质设计的生物工程与药物研发场景。

设计能折叠成目标三维结构的蛋白质序列,即蛋白质逆折叠,是蛋白质工程中的核心挑战。尽管近期深度学习方法已能有效恢复天然序列,但常忽略该问题的一对多特性:多个不同序列可折叠为同一结构。这促使需要一种能生成多样序列同时保持结构一致性的生成模型。为此,我们提出ProtInvTree,首个基于奖励引导的树搜索框架用于蛋白质逆折叠。ProtInvTree将序列生成重构为有意识的逐步决策过程,通过自评估、前瞻与回溯探索多条设计路径并挖掘优质候选。我们提出两阶段聚焦-锚定动作机制,解耦位置选择与残基生成。为高效评估中间状态,引入跳跃去噪策略,避免完整展开。基于预训练蛋白质语言模型,ProtInvTree支持灵活的测试时扩展,通过增加搜索深度和广度实现性能提升,无需重新训练。实验证明,ProtInvTree在多个基准上优于当前最优基线,生成结构一致但多样性高的序列,包括远偏离天然序列的样本。

原文摘要 · Abstract (English)

Designing protein sequences that fold into a target 3D structure, known as protein inverse folding, is a fundamental challenge in protein engineering. While recent deep learning methods have achieved impressive performance by recovering native sequences, they often overlook the one-to-many nature of the problem: multiple diverse sequences can fold into the same structure. This motivates the need for a generative model capable of designing diverse sequences while preserving structural consistency. To address this trade-off, we introduce ProtInvTree, the first reward-guided tree-search framework for protein inverse folding. ProtInvTree reformulates sequence generation as a deliberate, step-wise decision-making process, enabling the exploration of multiple design paths and exploitation of promising candidates through self-evaluation, lookahead, and backtracking. We propose a two-stage focus-and-grounding action mechanism that decouples position selection and residue generation. To efficiently evaluate intermediate states, we introduce a jumpy denoising strategy that avoids full rollouts. Built upon pretrained protein language models, ProtInvTree supports flexible test-time scaling by expanding the search depth and breadth without retraining. Empirically, ProtInvTree outperforms state-of-the-art baselines across multiple benchmarks, generating structurally consistent yet diverse sequences, including those far from the native ground truth.

蛋白质设计树搜索生成模型逆折叠

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