Rapid Alchemical Free Energy Calculation Employing a Generalized Born Implicit Solvent Model

摘要

Generalized Born (GB) implicit solvent models are typically used in postprocessing of molecular dynamics trajectories obtained from explicit solvent simulations to estimate binding free energies or effects of mutations in proteins. The possibility to employ a GB implicit solvent model for the calculation of rigorous free energy changes associated with alchemical transformations has been explored. During free energy perturbation (FEP) simulations, Lennard-Jones, Coulomb, and Born radii parameters are transformed gradually in a single-topology series. The FEP calculations are embedded in a replica exchange scheme allowing rapid convergence. The method was tested on the calculation of relative hydration free energies, relative binding free energies of a ligandreceptor system, and in silico alanine scanning of a peptideprotein complex. In all cases, good agreement with available experimental data was obtained. On medium sized proteinligand systems and using a cluster of graphical processing units, the approach allows the calculation of relative free energy changes associated with a chemical modification of a binding partner within a few minutes of computer time and opens the possibility for systematic in silico studies.