Protein Titration Benchmark of CHARMM36, Amber99sb-ildn, Amber14sb, OPLS-AA/M, and Martini 2 Force Fields for...

Constant pH molecular dynamics (CpHMD) has emerged as a powerful method for simulating pH-dependent processes in proteins and other biomolecules. The original implementation of the PME-based CpHMD in the GROMACS software included the CHARMM36 and Martini 2 force fields for the treatment of the titratable amino acids in proteins. As requested by the user community, this work contains the parametrization of titratable residues for the Amber99sb-ildn, Amber14sb, and OPLS-AA/M force fields. In addition to carefully carrying out the parametrization process, the performance of the different force fields in the scope of CpHMD is evaluated by performing computational titrations for a set of benchmark proteins. The calculated pKa values obtained using all force fields yield an average root-mean-square error of about 1 pH unit in comparison to experimental pKa values, which is in line with previous CpHMD benchmarks. The presented work expands the applicability of the PME-based CpHMD method in GROMACS and guides the researchers aiming to perform accurate and efficient CpHMD simulations.