AlphaFold2 Can Predict Single-Mutation Effects

AlphaFold2 (AF) is a promising tool, but is it accurate enough to predict single mutation effects? Here, we report that the localized structural deformation between protein pairs differing by only 1–3 mutations—as measured by the effective strain—is correlated across 3901 experimental and AF-predicted structures. Furthermore, analysis of ∼11 000 proteins shows that the local structural change correlates with various phenotypic changes. These findings suggest that AF can predict the range and magnitude of single-mutation effects on average, and we propose a method to improve precision of AF predictions and to indicate when predictions are unreliable.Received 3 January 2023Accepted 26 September 2023DOI:https://doi.org/10.1103/PhysRevLett.131.218401© 2023 American Physical SocietyPhysics Subject Headings (PhySH)Research AreasConformation changesProtein foldingProtein structureProtein structure predictionSecondary structureSequencing analysisTertiary structurePhysical SystemsProteinsTechniquesArtificial neural networksStatistical methodsPhysics of Living SystemsInterdisciplinary Physics