To this end, we use pmx-based NEQ free energy calculations to compute the ∆∆G and corresponding pK a values (as described in Equation ) for 144 residues across 13 different proteins in two contemporary force fields. The calculated free energy differences were combined into a consensus estimate. We also consider six popular and well-validated alternative computational methods as a comparison. Additionally, we compare our results to pK a values computed using FEP+ (Schr ödinger Inc.) and observe no statistically significant difference between the accuracy achieved with both methods.