Expanding gmx_MMPBSA capabilities for end-state binding free energy calculations with GROMACS and AMBER

Abstract

gmx_MMPBSA is an end-to-end tool for performing end-state binding free energy calculations. Here, we present advances in the gmx_MMPBSA suite that simplify preparation, expand the calculation options, and improve the analysis of results. The new features include the GBNSR6 and nonlinear PB models, second-order cumulant (C2) entropy estimation, inclusion of explicit structural waters, and multiple alanine/glycine mutations. We also introduce amber_MMPBSA, a new entry point that accepts native AMBER input files and extends the calculation and analysis capabilities of gmx_MMPBSA to AMBER users. The redesigned graphical analyzer, gmx_MMPBSA_ana, and modernized Python API facilitate exploration of large datasets and comparisons across multiple systems. We illustrate the new gmx_MMPBSA capabilities using a diverse set of biomolecular complexes (protein-protein, protein-RNA, protein-small molecule, DNA-small molecule) and show how the calculated binding energies vary across systems depending on the methodological choices. The source code is available at https://github.com/Valdes-Tresanco-MS/gmx_MMPBSA.