Kinetics of protein-ligand unbinding: Predicting pathways, rates, and rate-limiting steps.

ABSTRACT: The ability to predict the mechanisms and the associated rate constants of protein-ligand unbinding is of great practical importance in drug design. In this work we demonstrate how a recently introduced metadynamics-based approach allows exploration of the unbinding pathways, estimation of the rates, and determination of the rate-limiting steps in the paradigmatic case of the trypsin-benzamidine system. Protein, ligand, and solvent are described with full atomic resolution. Using metadynamics, multiple unbinding trajectories that start with the ligand in the crystallographic binding pose and end with the ligand in the fully solvated state are generated. The unbinding rate k off is computed from the mean residence time of the ligand. Using our previously computed binding affinity we also ob

SUBMITTER: Tiwary P 

PROVIDER: S-EPMC4321287 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature