Performance of the IEF-MST solvation continuum model in the SAMPL2 blind test prediction of hydration and tautomerization free energies

Abstract

The IEF-MST continuum solvation model is used to predict the hydration free energies and tautomeric preferences of a set of multifunctional compounds compiled as a blind test for computational solvation methods in the SAMPL2 contest. Computations of hydration free energies was performed using both HF/6-31G(d) and B3LYP/6-31G(d) versions of the IEF-MST model. For tautomeric preferences, the IEF-MST data was combined with the gas phase free energy differences predicted at different levels of theory ranging from MP2/6-31+G(d) to MP2/CBS+[CCSD-MP2/6-31+G(d)] levels. Comparison with the experimental data provided for hydration free energies yields a root-mean square deviation (rmsd) close to 2.3 kcal/mol, which is quite remarkable, especially considering the reduced set of training compounds used in the parametrization of the IEF-MST method. With regard to tautomerism, the lowest error in the prediction of the relative stabilities between tautomers in solution is obtained by combining MP2/CBS+[CCSD-MP2/6-31+G(d)] results with IEF-MST hydration free energies, yielding a rmsd of ca. 3.4 kcal/mol. The results illustrate the delicate balance that must be kept between the intrinsic relative stabilities in the gas phase and the differential hydration preferences in order to obtain an accurate description of the prototropic tautomerism in bioorganic compounds.