Alchemical free energy calculation methods have grown as essential techniques to pursue thermodynamic predictions in the field of drug discovery, peptide-ligand binding prediction, and ligand solvation free energy. The free energy difference between the two states can be predicted using free energy perturbation, thermodynamic integration, and λ dynamics, and the absolute and the relative approach can be chosen to deal with alchemical coupling parameter λ. Because the different simulation packages use different method and approach with various simulation technique for the binding free energy calculation, the ways to prepare initial modeling and corresponding input files are diverse. Moreover, the preparation of relative binding free energy systems using multiple ligand structures is not easy due to the hybridization of structures and topologies in a given combination. For these reasons, an automated setup tool for preparation of alchemical free energy calculation with proven and tested option values is essential. Herein, we describe the overall process of the CHARMM-GUI Ligand Binder modules that help the preparation of absolute and relative binding free energy calculation systems with all corresponding input files and force field parameters for CHARMM, NAMD, AMBER, and GENESIS programs. Besides, Ligand Binder allows users to upload multiple ligands at one time to save the time from the recursive process during the preparation of a large number of systems using the different ligands in the same protein. The benchmark results of binding free energy using different programs are shown to check the reliability of Ligand Binder in comparison with published binding free energy data.

CHARMM-GUI ligand binder for computing absolute & relative binding free energy

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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