Absolute and relative pKa predictions via a DFT approach applied to the SAMPL6 blind challenge

Abstract

In this work, quantum mechanical methods were used to predict the microscopic and macroscopic pK_a values for a set of 24 molecules as a part of the SAMPL6 blind challenge. The SMD solvation model was employed with M06-2X and different basis sets to evaluate three pK_a calculation schemes (direct, vertical, and adiabatic). The adiabatic scheme is the most accurate approach (RMSE = 1.40 pK_a units) and has high correlation (R² = 0.93), with respect to experiment. This approach can be improved by applying a linear correction to yield an RMSE of 0.73 pK_a units. Additionally, we consider including explicit solvent representation and multiple lower-energy conformations to improve the predictions for outliers. Adding three water molecules explicitly can reduce the error by 2-4 pK_a units, with respect to experiment, whereas including multiple local minima conformations does not necessarily improve the pK_a prediction.

Keywords: Implicit solvent; Quantum chemistry; SAMPL6; pK a.

Figure 1.

Thermodynamic cycles used for pK_a calculation schemes.

Figure 2.

Structures of the 24 molecules in the SAMPL6 pK_a challenge.

Figure 3.

Effect of microsolvation on pK_a calculations schemes for SM01.