Comparison with a recent GROMACS-based CpHMD implementation 37 also revealed a good pK a prediction accuracy for coupled residues. This result suggests that both CpHMD and alchemical free energy methods can resolve pK a values in both coupled and uncoupled contexts. We note that CpHMD has the distinct advantage that all residues can be simultaneously assessed for coupling, and deprotonation can dynamically occur over the course of a simulation due to structural changes in the protein or environment. This allows for the resolution of potentially more complex biophysical pheneomena that could rely on protein dynamics. On the other hand CpHMD simulations can be computationally expensive and here, we demonstrate, that sometimes similar insights can be extracted from "plain" molecular dynamics simulations paired with alchemical free energy methods.