As ∆∆G values can be obtained by means of alchemical free energy calculations, the presented approach allows for a convenient estimation of coupled residue pK a s in practice. We demonstrate that our approach and a previously proposed microscopic pK a formalism, can be combined with alchemical free energy calculations to resolve pH-dependent protein pK a values. Toy models and both, regular and constant-pH molecular dynamics simulations, alongside experimental data, are used to validate this approach. Our results highlight the insights gleaned when coupling and microstate probabilities are analyzed and suggest extensions to more complex enzymatic contexts. Furthermore, we find that n äively computed pK a values that ignore coupling, can be significantly improved when coupling is accounted for, in some cases reducing the error by half. In short, alchemical free energy methods can resolve the pK a values of both uncoupled and coupled residues.