pK-Yay: A Black-Box Method Using Density Functional Theory and Implicit Solvation Models to Compute Aqueous pK_a...

The concept of pK_a is very important in chemistry and biology. Over the past two decades, electronic structure calculations have made huge strides toward becoming reliable counterparts to experiments in determining solution-phase pK_a values. However, invariably, the computation of pK_a values involves the use of methods whose error bars are intrinsically larger (definitely >2 kcal/mol with density functionals) than the accuracy desired for the estimation of pK_a values (<1 or 1.5 pK_a units). This scenario presents an ample scope for innovation in developing systematic error cancellation methods even today. In this work, we have developed the pK-Yay method. It is a user-friendly black-box method used to compute aqueous pK_a values of strong and weak acids employing routinely used and computationally inexpensive density functionals and implicit solvation models. It does not require the use of any explicit solvent molecule or modifying any other parameter in an electronic structure program. As part of evaluating the method, a comprehensive test set of 26 weak and strong organic and mineral acids covering 35 pK_a units (20 to -15) was assembled. The detailed description of the method, its performance with different functionals (ωB97X-D performed best for organic acids with a mean absolute error (MAE) of 0.8 pK_a units, and B2-PLYP performed best for strong acids with an MAE of 1.6 pK_a units), the strengths and limitations in the present version, and a future scope to improve the accuracy and reduce its empirical nature are presented herein.