We constructed a hybrid Amber14SB-K force field with the altered lysine partial charges, but only for the probed residue. We found that this force field performed markedly better on the lysine dataset, cutting the average unsigned error by almost half, from 1.48 ± 0.18 pK to 0.81 ± 0.08 pK (Figure ). This result, in addition to that from Best et al. , suggested the default partial charges of lysine were erroneous. To further assess the effect of partial charges, we computed the thermostability of 15 lysine mutations using CHARMM36m, Amber14SB, and Amber14SB-K. We again observed a marked improvement in the AUE using the altered lysine partial charges, which shifted the value from 10.42 kJ/mol to 5.54 kJ/mol (Figure ). While Amber99SB-disp exhibited the highest accuracy on the lysine dataset (Figure ), suggesting its general use for pK a prediction, this behaviour did not hold for aspartate and glutamate.