- Peng Lian, The University of Tennessee, Knoxville
Developing accurate quantum chemistry-based approaches for calculating pKa’s is of great interest for modeling and experimental applications. Various methods have been proposed to increase the accuracy of pKa calculated by DFT and continuum solvation models, i.e. regression-based fitting, inclusion of explicit water molecules and construction of thermodynamic cycles. These methods perform well, but they either need to introduce additional degrees of freedom or could not generalize well. Based on the current SMD model, we used the scaled solvent accessible surface (sSAS) and an optimized scaling factor α to rebuild the solute-solvent boundary and further to improve the accuracy in quantum chemical pKa calculations. Direct approach that avoids the gas phase calculations in the thermal cycle method in pKa calculations was used. To keep the number of degrees of freedom as low as possible, no explicit water molecules were included in any of the calculations. Three benchmark datasets of experimentally measured pKa values, including 28 carboxylic acids, 10 aliphatic amines, and 45 thiols were used to assess the optimized SMD model, which we call the SMD continuum solvent model with scaled solvent-accessible surface (SMD-sSAS). Of the methods tested, the M062X density functional approximation, 6-31+G(d,p) basis set, and SMD-sSAS provided the most accurate results for each set, yielding mean unsigned errors of 0.9, 0.4, and 0.5 pK units, respectively, for carboxylic acids, aliphatic amines, and thiols.
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