Linear Fitness Subspace in Protein Language Models Enables Sample-Efficient Directed Evolution
Year: 2026
Type: conference-paper
Abstract: 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 Prote-inGym assays, 87 extended static-validation assays, and an 18-assay budgeted-search evaluation, SGES improves fitness prediction and search efficiency over zero-shot PLMs and recent ML-guided protein optimization baselines.Controlled comparisons with PCA, random projections, label-shuffled PLS, classical mutation features, and acquisition ablations further isolate the benefit of a fitness-aligned site-delta coordinate.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W7220894630