In this work we explore the effects of coupling on the shifts in pK a between spatially neighbouring residues. We begin by illustrating the potential magnitude of such effects on a set of toy systems by systematically altering coupling strength. We then focus on two proteins where similar coupling behaviour between amino acid residues are observed. We demonstrate that explicitly accounting for the coupling between titratable sites significantly improves accuracy of the pK a prediction and highlight the potential insights associated with coupling analysis (e.g., buffering between residues). Finally, we provide a practical guide for using alchemical free energy calculations to: 1) account for pK a shifts in coupled residues based on the formalism derived in this work; and 2) compute the probabilities of individual protonation microstates based on an existing partition function framework.