Recently we demonstrated that atomistic molecular dynamics simulations paired with nonequilibrium alchemical free energy calculations are capable of accurately resolving the pK a values of aspartate, glutamate, and lysine. Here, we assess the ability of our pmx-based, nonequilibrium switching (NES) approach to calculate the pK a values of 40 cysteines and 22 histidines across a range of wildtype and mutant proteins. We compare our results to two conventional predictor methods and the previously reported performance of three MD-based approaches, chosen because it more accurately reproduces the relevant bulk properties of water compared to conventional 3-point models (i.e., TIP3P). The result of these classical simulations was a final cubic box size of L = 15 Å, containing 109 water molecules and a methylthiolate molecule.