Ensemble-Based Replica Exchange Alchemical Free Energy Methods: The Effect of Protein Mutations on Inhibitor Binding.

ABSTRACT: The accurate prediction of the binding affinity changes of drugs caused by protein mutations is a major goal in clinical personalized medicine. We have developed an ensemble-based free energy approach called thermodynamic integration with enhanced sampling (TIES), which yields accurate, precise, and reproducible binding affinities. TIES has been shown to perform well for predictions of free energy differences of congeneric ligands to a wide range of target proteins. We have recently introduced variants of TIES, which incorporate the enhanced sampling technique REST2 (replica exchange with solute tempering) and the free energy estimator MBAR (Bennett acceptance ratio). Here we further extend the TIES methodology to study relative binding affinities caused by protein mutations when bound to

SUBMITTER: Bhati AP 

PROVIDER: S-EPMC6447239 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature