Titr-DMD – A Rapid, Coarse-Grained Quasi-All-Atom Constant pH Molecular Dynamics Framework

The pH dependence of enzyme fold stability and catalytic activity is a fundamentally dynamic, structural property which is difficult to study. Computational methods, particularly constant pH molecular dynamics (CpHMD), are the best situated tools for this. However, these often struggle with affordable sampling of sufficiently long timescales, accuracy of pKa prediction, and verification of the structures they generate. We introduce Titr-DMD, an affordable CpHMD method with a protonation state sampler that can be systematically improved, to circumvent these issues. We benchmark the method on a set of proteins with experimentally attested pKa and on the pH triggered conformational change in a staphylococcal nuclease mutant, a rare experimental study of such behavior. Our results show Titr-DMD to be an effective method to study pH coupled protein dynamics.