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

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 subtrajectories. Each change in the protoriation state of the molecule at the beginning of a Dew 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 pK(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. (C) 2004 Elsevier B.V. All rights reserved.