Constant pH Replica Exchange Molecular Dynamics in Biomolecules Using a Discrete Protonation Model

A constant pH replica exchange molecular dynamics (REMD) method is proposed and implemented to improve coupled protonation and conformational state sampling. By mixing conformational sampling at constant pH (with discrete protonation states) with a temperature ladder, this method avoids conformational trapping. Our method was tested and applied to seven different biological systems. The constant pH REMD not only predicted pK(a) correctly for small, model compounds but also converged faster than constant pH molecular dynamics (MD). We further tested our constant pH REMD on a heptapeptide from the ovomucoid third domain (OMTKY3). Although constant pH REMD and MD produced very cic se pKa values, the constant pH REMD showed its advantage in the efficiency of conformational and protonation state samplings.