Accurate Estimation of pKb Values for Amino Groups from Surface Electrostatic Potential (VS,min) Calculations: The Isoelectric Points of Amino Acids as a Case Study.

Theoretical calculation of equilibrium dissociation constants is a very computationally demanding and time-consuming process since it requires an extremely accurate computation of the solvation free energy changes for each of the species involved. By correlating the minimum surface electrostatic potential (VS,min) on the nitrogen atom of several aliphatic amino groups-calculated at the density functional theory (DFT) ωB97X-D/cc-pVDZ level of theory-we obtained regression models for each kind of substitution pattern from which we interpolate their corresponding pKb values with remarkable accuracy: primary R2 = 0.9519; secondary R2 = 0.9112; and tertiary R2 = 0.8172 (N = 20 for each family). These models were validated with tests sets (N = 5) with mean absolute error (MAE) values of 0.1213 (primary), 0.4407 (secondary), and 0.3057 (tertiary). Combining this ansatz with another previously reported by our group to estimate pKa values [Caballero-García, G.; et al. Molecules 2019, 24(1), 79] we are able to reproduce the isoelectric points of 13 amino acids with no titrable side chains with MAE = 0.4636 pI units.