Prediction of pK(a) shifts without truncation of electrostatic interactions: An explicit solvent calculation for succinic acid

The prediction of pK(a) shifts from molecular models which incorporate solvent effects is a subject of renewed interest in biophysical chemistry. We have computed the difference in pK(a)'s in succinic acid by an explicit solvent molecular dynamics simulation with Ewald summation and obtained results that are very close to the experimental value. The effects of conformational averaging are also considered by including both the trans and gauche conformers of succinic acid. For comparison, continuum electrostatic calculations for the pK(a) shift in succinic acid were also carried out. The interaction free energy between the charged groups is overestimated when a standard small molecule value (epsilon(i) = 2) is used to model the internal dielectric of the diacid. Although the explicit solvent simulations of pK(a) shifts are more expensive in terms of computer time, the predictive power of these simulations has now progressed to the point where comparisons between explicit and continuum solvent models can reveal differences which have their true physical origin in the inherent molecularity of the surrounding medium.