Relative Binding Free Energy between Chemically Distant Compounds Using a Bidirectional Nonequilibrium Approach.

ABSTRACT: In the context of advanced hit-to-lead drug design based on atomistic molecular dynamics simulations, we propose a dual topology alchemical approach for calculating the relative binding free energy (RBFE) between two chemically distant compounds. The method (termed NE-RBFE) relies on the enhanced sampling of the end-states in bulk and in the bound state via Hamiltonian Replica Exchange, alchemically connected by a series of independent and fast nonequilibrium (NE) simulations. The technique has been implemented in a bidirectional fashion, applying the Crooks theorem to the NE work distributions for RBFE predictions. The dissipation of the NE process, negatively affecting accuracy, has been minimized by introducing a smooth regularization based on shifted electrostatic and Lennard-Jones non

SUBMITTER: Procacci P 

PROVIDER: S-EPMC9202353 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature