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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 (pKa 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 pKa 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.