Linear Fitness Subspace in Protein Language Models Enables Sample-Efficient Directed Evolution

SiYuan Ma, Canran Xiao, Zikai Xiao, Albert Gao, Liang He +3

Model-guided directed evolution seeks to identify high-fitness protein variants under limited oracle budgets. Protein language models (PLMs) provide rich representations for this task, but task-agnostic zero-shot scores can be misaligned with a target assay, while supervised search in high-dimensional embedding spaces can make surrogate modeling and uncertainty estimation sample-inefficient. We propose the Linear Fitness Subspace (LFS) hypothesis: within mutation-induced residue-level representation changes, a compact, assay-specific set of directions makes fitness variation linearly accessible from few labeled variants. This is a local, supervision-recoverable statement rather than a claim that protein fitness landscapes or global PLM geometry are universally linear. Building on this observation, we introduce Subspace-Guided Evolutionary Search (SGES), which estimates an LFS from a small initial sample and performs surrogate modeling, uncertainty estimation, and acquisition in the learned subspace. Across 10 core ProteinGym assays, 87 extended static-validation assays, and an 18-assay budgeted-search evaluation, SGES improves fitness prediction and search efficiency over…