Authors

Abstract

Alchemical free energy simulations have long been utilized to predict free energy changes forbinding affinity and solubility of small molecules. However, while the theoretical foundation ofthese methods is well established, seamlessly handling many of the practical aspects regardingthe preparation of the different thermodynamic end states of complex molecular systems and ofthe numerous processing scripts often remain a burden for successful applications. In this work,we present CHARMM-GUI Free Energy Calculator (http://​www​.char​mm​-gui​.org/​i​n​p​u​t/fec) thatprovides various alchemical free energy perturbation molecular dynamics (FEP/MD) systemswith input and post-processing scripts for NAMD and GENESIS. Four submodules are available:Absolute Ligand Binder (for absolute ligand binding FEP/MD), Relative Ligand Binder (forrelative ligand binding FEP/MD), Absolute Ligand Solvator (for absolute ligand solvationFEP/MD), and Relative Ligand Solvator (for relative ligand solvation FEP/MD). Each module isdesigned to build multiple systems of a set of selected ligands at once for high-throughputFEP/MD simulations. The capability of Free Energy Calculator is illustrated by absolute andrelative solvation FEP/MD of a set of ligands and absolute and relative binding FEP/MD of a setof ligands for T4 lysozyme in solution and adenosine A2A receptor in a membrane. Thecalculated free energy values are overall consistent with the experimental and published freeenergy results (within ~1 kcal/mol). We hope that Free Energy Calculator is useful to carry outhigh-throughput FEP/MD simulations in the field of biomolecular sciences and drug discovery.