Evolutionary Constraints Guide AlphaFold2 in Predicting Alternative Conformations and Inform Rational Mutation Design.

ABSTRACT: Investigating structural variability is essential for understanding protein biological functions. Although AlphaFold2 accurately predicts static structures, it fails to capture the full spectrum of functional states. Recent methods have used AlphaFold2 to generate diverse structural ensembles, but they offer limited interpretability and overlook the evolutionary signals underlying the predictions. In this work, we enhance the generation of conformational ensembles and identify sequence patterns that influence the alternative fold predictions for several protein families. Building on prior research that clustered multiple sequence alignments to predict fold-switching states, we introduce a refined clustering strategy that integrates protein language model representations with hierarchical c

SUBMITTER: Piomponi V 

PROVIDER: S-EPMC12458692 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature