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 (V_S,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 pK_b 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 pK_a 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.