Constant-pH Simulations with the Polarizable Atomic Multipole AMOEBA Force Field

Classical mechanical simulation of molecular models at constant pH is an advanced technique for studying conformational dynamics in the presence of proton titration which is critical to pharmaceutical design. The algorithms presented previously have been limited to fixed charge force fields. This work introduces the first constant pH molecular dynamics (CpHMD) algorithm compatible with multipolar electrostatics and polarizability. Additionally, our implementation in the open-source Force Field X software has the unique ability to handle titration state changes in crystalline systems, including flexible support for all 230 space groups. Evaluation of the constant pH AMOEBA model was performed on 11 crystal peptide systems that span the titrating amino acids Asp, Glu, His, Lys, and Cys. Accurate titration state predictions for these crystals, including for the coordination of Zn+2 by cysteines, demonstrates the promise of the method for constant pH molecular dynamics simulations of proteins in the context of pKa predictions, assessment of protein conformational ensembles, and for the calculation of protein-ligand binding affinity.