Resolution of a Challenge For Solvation Modeling: Calculation of Dicarboxylic Acid Dissociation Constants Using Mixed Discrete-Continuum Solvation Models

Marenich, A. V.; Ding, W.; Cramer, C. J.; Truhlar, D. G.

* J. Phys. Chem. Lett.*
**2012**, *3*, 1437
(doi:10.1021/jz300416r).

First and second dissociation constants (p*K*_{a} values) of
oxalic acid, malonic acid, and adipic acid were computed by using a number
of theoretical protocols based on density functional theory and using both
continuum solvation models and mixed discrete-continuum solvation models.
We show that fully implicit solvation models (in which the entire solvent
is represented by a dielectric continuum) fail badly for dicarboxylic acids
with mean unsigned errors (averaged over six p*K*_{a} values)
of 2.4-9.0 log units, depending on the particular implicit model used. The
use of water-solute clusters and accounting for multiple conformations in
solution significantly improves the performance of both generalized Born
solvation models and models that solve the nonhomogeneous-dielectric
Poisson equation for bulk electrostatics. The four most successful models
have mean unsigned errors of only 0.6-0.8 log units.