Two potential limitation of CpHMD simulations are the computational cost and ability to integrate such a method into existing alchemical free energy frameworks. An alchemical approach based entirely on free energy calculations avoids the need for many simulations across a pH spectrum, instead allowing one to resolve the individual coupled pK a s by computing only three ∆∆G values. As alluded to, a key motivation of relying on alchemical free energies is that a coupled pK a prediction scheme can be seamlessly integrated into existing workflows (e.g., pmx, FEP+, etc.).