Protein structure shapes natural genetic variation and <i>de novo</i> adaptation.

ABSTRACT: Protein structural context strongly influences the functional outcomes of mutations, but exploiting this intuition to interpret the consequences of natural variants has been limited by the paucity of structural information. Here, we show that simple molecular heuristics based on predicted protein structures-solvent accessibility and the local complexity of the protein fold-are strong predictors of protein-coding variation in genomes from yeast to plants to humans. Polymorphisms in structured and unstructured regions alike were subject to these constraints, revealing fine-grained selection across amino acid residues and secondary structures. The same analyses distinguished deleterious variants in datasets from existing deep mutational scans. Extending the metrics to de novo adaptatio

SUBMITTER: Jakobson CM 

PROVIDER: S-EPMC12776117 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature