Probing Functional Allosteric States and Conformational Ensembles of the Allosteric Protein Kinase States and Mutants: Atomistic Modeling and Comparative Analysis of AlphaFold2, OmegaFold, and AlphaFlow Approaches and Adaptations

This study reports a comprehensive analysis and comparison of several AlphaFold2 adaptations and OmegaFold and AlphaFlow approaches in predicting distinct allosteric states, conformational ensembles, and mutation-induced structural effects for a panel of state-switching allosteric ABL mutants. The results revealed that the proposed AlphaFold2 adaptation with randomized alanine sequence scanning can generate functionally relevant allosteric states and conformational ensembles of the ABL kinase that qualitatively capture a unique pattern of population shifts between the active and inactive states in the allosteric ABL mutants. Consistent with the NMR experiments, the proposed AlphaFold2 adaptation predicted that G269E/M309L/T408Y mutant could induce population changes and sample a significant fraction of the fully inactive I