Using Amber14SB-1.3σ on the full dataset gave an AUE of 2.88 ± 0.35 pK and a Pearson correlation of 0.20 ± 0.11: markedly improved from the performance of plain Amber14SB, but still worse than the accuracy previously reported for aspartate, glutamate, and lysine. Using the σ-value that maximized agreement with the ab initio determined solvation structure (i.e., σ = 1.1), yielded an AUE of 3.28 ± 0.42 pK and a Pearson correlation of 0.35 ± 0.02. This shift is consistent with previous work that found a 0.5 pK improvement using a similar scaling factor for Amber99SB. We performed an identical analysis for CHARMM36m, which indicated that although a larger σ value (i.e., σ ≈ 1.15) was required to achieve an accurate experimental solvation free energy (Figure ), the default LJ parameters could effectively reproduce the RDF data (Figure ) and maximize pK a prediction accuracy on the DsbA test set (Figure ); this observation led us to leave the σ parameter untouched. Using the OPC water model (rather than mTIP3P) resulted in an identical position of the first solvation shell (Figure ) and suggested the same scaling factor was required to reproduce the experimental solvation free energy (Figure ).