arXiv:2510.07286cs.LGcs.AI2025-10

用进化信号提升蛋白质突变适应度预测,仅用少量数据达顶尖性能。

Evolutionary Profiles for Protein Fitness Prediction

  • 将自然进化视为奖励最大化,把语言模型训练看作逆强化学习。
  • 在217个实验上表现领先,仅用0.15%数据和更少参数。
  • 融合家族内与跨家族进化信息,对不同蛋白类型更鲁棒。

预测突变对蛋白质适应度的影响是蛋白质工程的核心挑战,但实验数据远少于序列空间规模。基于掩码语言建模(MLM)训练的蛋白质语言模型(pLMs)表现出强大的零样本适应度预测能力。本文将自然进化解释为隐式奖励最大化,而MLM可视为逆强化学习(IRL),其中现存序列作为专家示范,pLM对数似然值则作为适应度估计。基于此视角,提出EvoIF:一种轻量级模型,融合两类互补的进化信号:(i) 从同源序列中获取的家族内频率谱;(ii) 从反折叠逻辑回归中提取的跨家族结构-进化约束。EvoIF通过紧凑的转换模块融合序列-结构表示与上述谱图,生成校准后的对数似然概率评分。在ProteinGym数据集(217个突变实验;超过250万突变体)上,EvoIF及其启用多序列比对(MSA)的变体达到当前最优或竞争力水平,且仅使用0.15%的训练数据,参数量低于近期大型模型。消融实验证明,家族内与跨家族信号具有互补性,显著提升在不同功能类型、MSA深度、物种及突变深度下的鲁棒性。代码将公开。

原文摘要 · Abstract (English)

Predicting the fitness impact of mutations is central to protein engineering but constrained by limited assays relative to the size of sequence space. Protein language models (pLMs) trained with masked language modeling (MLM) exhibit strong zero-shot fitness prediction; we provide a unifying view by interpreting natural evolution as implicit reward maximization and MLM as inverse reinforcement learning (IRL), in which extant sequences act as expert demonstrations and pLM log-odds serve as fitness estimates. Building on this perspective, we introduce EvoIF, a lightweight model that integrates two complementary sources of evolutionary signal: (i) within-family profiles from retrieved homologs and (ii) cross-family structural-evolutionary constraints distilled from inverse folding logits. EvoIF fuses sequence-structure representations with these profiles via a compact transition block, yielding calibrated probabilities for log-odds scoring. On ProteinGym (217 mutational assays; >2.5M mutants), EvoIF and its MSA-enabled variant achieve state-of-the-art or competitive performance while using only 0.15% of the training data and fewer parameters than recent large models. Ablations confirm that within-family and cross-family profiles are complementary, improving robustness across function types, MSA depths, taxa, and mutation depths. The codes will be made publicly available.

蛋白质工程进化信号适应度预测轻量模型

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