Recent development and application of constant pH molecular dynamics

Abstract

Solution pH is a critical environmental factor for chemical and biological processes. Over the last decade, significant efforts have been made in the development of constant pH molecular dynamics (pHMD) techniques for gaining detailed insights into pH-coupled dynamical phenomena. In this article we review the advancement of this field in the past five years, placing a special emphasis on the development of the all-atom continuous pHMD technique. We discuss various applications, including the prediction of pK_a shifts for proteins, nucleic acids and surfactant assemblies, elucidation of pH-dependent population shifts, protein-protein and protein-RNA binding, as well as the mechanisms of pH-dependent self-assembly and phase transitions of surfactants and peptides. We also discuss future directions for the further improvement of the pHMD techniques.

Keywords: algorithms; electrostatics; molecular dynamics; pH; pKa calculation.

Figure 1

All-atom CpHMD simulation of BBL protein. Upper : BBL in the simulation box filled with water. Titratable water molecules are highlighted in the van der Waals representation. Lower : Simulated titration curves for carboxyl and histidine sidechains.

Figure 2

Structure of the N100K mutant of SNase protein. Lys100 is shown in the van der Waals representation.

Figure 3

Coupling of protonation equilibria with conformational exchange. A and B refer to the closed and open states of the N100K mutant of SNase, respectively. AH⁺ and BH⁺ refer to the respective charged forms when Lys100 is protonated.