Constant pH replica exchange molecular dynamics study of protein structure and dynamic

Solution pH is a very important thermodynamic variable that affects protein structure, function and dynamics. Enormous effort has been made experimentally and computationally to understand the effect of pH on proteins. One category of computational method to study the effect of pH is the constant-pH molecular dynamics (constant-pH MD) methods. Constant-pH MD employs dynamic protonation in simulations and correlates protein conformations and protonation states. Therefore, constant-pH MD algorithms are able to predict pKa value of an ionizable residue as well as to study pH-dependence directly.;A replica exchange constant-pH molecular dynamics (constant-pH 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 on seven different biological systems. The constant-pH REMD not only predicted pKa correctly for model peptides but also converged faster than constant pH MD. Furthermore, the constant-pH REMD showed its advantage in the efficiency of conformational samplings. The advantage of utilizing constant-pH REMD is clear.;We have studied the effect of pH on the structure and dynamics of C-peptide from ribonuclease A by constant-pH REMD. The mean residue ellipticity at 222 nm at each pH value is computed, as a direct comparison with experimental measurements. The C-peptide conformational ensembles at pH 2, 5, and 8 are studied. The Glu2-Arg10 and Phe8-His12 interactions and their roles in the helix formation are also investigated.;Constant-pH REMD method is applied to the study of hen egg white lysozyme (HEWL). pKa values are calculated and compared with experimental values. Factors that could affect pK a prediction such as hydrogen bond network and interaction between ionizable residues are discussed. Structural feature such as coupling between conformation and protonation states is demonstrated in order to emphasize the importance of accurate sampling of the coupled conformations and protonation states.