Although the pK int is pH-independent, it may still provide a strong estimate of the true pK a depending on the reference protonation state assigned to the protein. Indeed, recent work has demonstrated that alchemical free energy calculations can resolve protein pK a values relying on the assumption: pK a ≈ pK int . Nevertheless, it is inevitable that in some instances this will break down, and only by considering ∆G titr (pH) can an accurate pK a be resolved. Here, we investigate whether coupling can be meaningfully resolved within an alchemical free energy framework and assess the relative importance of this contribution for computing protein pK a values.