Accounting for the Central Role of Interfacial Water in Protein-Ligand Binding Free Energy Calculations.

ABSTRACT: Rigorous binding free energy methods in drug discovery are growing in popularity because of a combination of methodological advances, improvements in computer hardware, and workflow automation. These calculations typically use molecular dynamics (MD) to sample from the Boltzmann distribution of conformational states. However, when part or all of the binding sites is inaccessible to the bulk solvent, the time needed for water molecules to equilibrate between bulk solvent and the binding site can be well beyond what is practical with standard MD. This sampling limitation is problematic in relative binding free energy calculations, which compute the reversible work of converting ligand 1 to ligand 2 within the binding site. Thus, if ligand 1 is smaller and/or more polar than ligand 2, the per

SUBMITTER: Ben-Shalom IY 

PROVIDER: S-EPMC7725968 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature