Chapter 1 Molecular Simulations of pH-Mediated Biological Processes

Publisher Summary This chapter discusses the recent development of a pH-coupled molecular dynamics technique, called “continuous constant pH molecular dynamics” (CPHMD), and its applications to first principles p K a calculations and pH-coupled biological phenomena. Conformational dynamics and acid–base equilibria are microscopically coupled. However, traditional molecular dynamics simulations are performed with fixed protonation states. The development of CPHMD has improved the physical realism in molecular simulations. It has enabled, for the first time, quantitative p K a prediction for biological macromolecules on a first-principles level, thereby eliminating the need for ad hoc assignment of a protein dielectric constant and for a high-resolution structure as in the traditional Poisson–Boltzmann based approaches. Despite this success, the accuracy of the CPHMD method can be further improved through the continuing development of the underlying generalized Born (GB) implicit solvent model and its parameterization. The underestimation of pKa shifts for deeply buried residues may be reduced by using a molecular surface that accounts for the solvent excluded volume.