Addressing Intersite Coupling Unlocks Large Combinatorial Chemical Spaces for Alchemical Free Energy Methods.

ABSTRACT: Alchemical free energy methods are playing a growing role in molecular design, both for computer-aided drug design of small molecules and for computational protein design. Multisite λ dynamics (MSλD) is a uniquely scalable alchemical free energy method that enables more efficient exploration of combinatorial alchemical spaces encountered in molecular design, but simulations have typically been limited to a few hundred ligands or sequences. Here, we focus on coupling between sites to enable scaling to larger alchemical spaces. We first discuss updates to the biasing potentials that facilitate MSλD sampling to include coupling terms and show that this can provide more thorough sampling of alchemical states. We then harness coupling between sites by developing a new free energy estimator base

SUBMITTER: Hayes RL 

PROVIDER: S-EPMC9700482 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature