Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations.

ABSTRACT: The majority of drug-like molecules contain at least one ionizable group, and many common drug scaffolds are subject to tautomeric equilibria. Thus, these compounds are found in a mixture of protonation and/or tautomeric states at physiological pH. Intrinsically, standard classical molecular dynamics (MD) simulations cannot describe such equilibria between states, which negatively impacts the prediction of key molecular properties in silico. Following the formalism described by de Oliveira and co-workers (J. Chem. Theory Comput. 2019, 15, 424-435) to consider the influence of all states on the binding process based on alchemical free-energy calculations, we demonstrate in this work that the multistate method replica-exchange enveloping distribution sampling (RE-

SUBMITTER: Champion C 

PROVIDER: S-EPMC11137823 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature