Constant-pH molecular dynamics simulations: a test case of succinic acid

Abstract

Abstract A method for performing constant-pH molecular dynamics (MD) simulations, with an implicit solvent and explicit treatment of protonation/deprotonation phenomena, is applied to a succinic acid molecule. The protonation state of each ionizable group in the molecule is allowed to change during the MD trajectory at predefined time intervals, dividing the whole simulation into a set of sub-trajectories. Each change in the protonation state of the molecule at the beginning of a new sub-trajectory is made with a probability determined by the electrostatic free energies of the available states, based on the last structure of the preceding sub-trajectory. Our simulations resulted in the distribution of conformational states of the molecule, and in its molecular p K a s, in good agreement with available experimental data. Moreover, dependence of the distribution of the trans /gauche conformers on the time interval selected for the sub-trajectories between making decisions regarding protonation states of the residues, indicates that this equilibrium is sensitive to the dynamics of proton exchange.