Equilibrium and Nonequilibrium Ensemble Methods for Accurate, Precise and Reproducible Absolute Binding Free Energy Calculations.

ABSTRACT: Free energy calculations for protein-ligand complexes have become widespread in recent years owing to several conceptual, methodological and technological advances. Central among these is the use of ensemble methods which permits accurate, precise and reproducible predictions and is necessary for uncertainty quantification. Absolute binding free energies (ABFEs) are challenging to predict using alchemical methods and their routine application in drug discovery has remained out of reach until now. Here, we apply ensemble alchemical ABFE methods to a large data set comprising 219 ligand-protein complexes and obtain statistically robust results with high accuracy (<1 kcal/mol). We compare equilibrium and nonequilibrium methods for ABFE predictions at large scale and provide a systematic criti

SUBMITTER: Bhati AP 

PROVIDER: S-EPMC11736689 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature