Enhancing Conformation and Protonation State Sampling of Hen Egg White Lysozyme Using pH Replica Exchange Molecular Dynamics.

We evaluate the efficiency of the pH replica exchange molecular dynamics (pH-REMD) method proposed by Itoh et al. (Proteins2011, 79, 3420-3436) by using it to predict the pKa values of the titratable residues in hen egg white lysozyme (HEWL). pKa values predicted using pH-REMD converge significantly faster than those calculated using constant pH molecular dynamics (CpHMD). Furthermore, increasing the frequency between exchange attempts in pH-REMD simulations improves protonation and conformational state sampling. By enabling the simulation to sample both conformational and protonation states more rapidly, pH-REMD simulations provide valuable insight into the pH-dependence of HEWL that the CpHMD simulations failed to capture. We present an efficient and highly scalable implementation of pH-REMD as an attractive enhancement to traditional CpHMD methods.