arXiv:2608.26419q-bio.QMcs.LG2026-08

用氨基酸骨架几何特征解析蛋白语言模型的隐藏表示,发现局部结构模式。

Interpreting Latent Protein Language Model Features with Geometric Annotations

论文配图:Interpreting Latent Protein Language Model Features with Geometric Annotations
图 1 · 摘自论文原文
  • 用Cα骨架几何特征自动标注SAE神经元激活模式。
  • 发现多个SAE特征与局部几何强相关,覆盖数据库未标注序列。
  • 可定位残基级结构特征,助力理解未知蛋白功能。

蛋白语言模型(pLMs)编码序列信息以支持结构预测等下游任务,但其内部表示机制仍不清晰。稀疏自编码器(SAEs)可将pLM表示分解为可解释特征,但现有标注方法多依赖数据库标签和顶级激活序列的LLM注释,易忽略残基级和几何层面的模式。本文提出一种自动化、可扩展的方法,利用蛋白质Cα骨架的几何特征解释ESM-2中的SAE特征。在ESM-2 8M各层中,经过FDR控制的发现分析显示,局部几何与众多SAE特征显著关联,预测强度各异,扩展了传统数据库和序列方法的覆盖范围。特别地,几何特征能区分具有相同数据库标注的SAE特征,揭示已知生物标签内的子结构。大量SAE特征激活于未标注的宏基因组蛋白序列,使我们得以通过SAE注释更深入理解这些序列。此外,接触预测消融实验表明,移除这些几何特征会使ESM-2的预测接触图朝描述方向偏移,验证了方法的可靠性。该方法实现了残基级的机制可解释性与结构生物学之间的桥梁。

原文摘要 · Abstract (English)

Protein language models (pLMs) encode information about protein sequences which enable downstream tasks such as structure prediction, but their internal representations are not well understood. Sparse autoencoders (SAEs) provide a promising tool to disentangle latent pLM representations into interpretable features, but existing annotation pipelines largely rely on protein-level annotations derived from database labels and LLM annotations of top activating sequences. Such annotations can overlook the localized residue-level and geometric patterns encoded by sparse features. We introduce an automated and scalable method for interpreting SAE features in ESM-2 by using geometrically inspired features of the protein $\text{C}_α$ backbone. Across ESM-2 8M layers, an FDR-controlled discovery analysis shows that local geometry is significantly associated with many SAE features, with varying levels of predictive strength, expanding coverage beyond database and sequence-based methods. In particular, geometry can distinguish SAE features sharing the same database annotation, revealing substructure within known biological labels. A significant portion of SAE features activate on unannotated metagenomic protein sequences enabling us to use our SAE annotations to better understand these sequences. In addition, ablation experiments at the level of contact prediction show that removing found geometric features shifts ESM-2's predicted contact maps in the direction of the descriptor. This provides a robust method of annotating proteins activated within SAE neurons at a residue level, providing a bridge between mechanistic interpretability and structural biology.

蛋白语言模型可解释性几何特征结构生物学

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