Accurate prediction of strongly perturbative mutation-induced structural changes

Develop methods that accurately predict mutant protein structures and the structural deformations induced by strongly perturbative single amino acid mutations from sequence information.

Background

The paper evaluates mutation-induced structural deformation using paired wild-type and single-amino-acid mutant X-ray crystal structures and assesses whether AlphaFold3 can reproduce those changes. Although AlphaFold3 performs moderately well across the full dataset, its accuracy decreases substantially for mutations producing structural deformations larger than the intrinsic fluctuations observed among wild-type duplicate structures.

The authors identify strongly perturbative mutations as a persistent unresolved challenge because the normalized change in relative solvent accessibility correlates with experimentally observed deformation but requires knowledge of the mutant structure itself. Consequently, a method that can predict the relevant mutant structural response, or informative physical features such as solvent accessibility changes, directly from sequence remains to be developed.