Explicitly accounting for residue coupling reduced the AUE from 1.28 pK to 0.76 pK of the residues considered, bringing the accuracy close to the AUE observed over the full dataset (Figure ). For all the methods considered, this coupled residue subset had higher errors than those observed on the remaining aspartate and glutamate residues (i.e., full dataset minus coupled subset). We note that this analysis was retrospective, where we have a priori access to the correct pK a values, i.e. we could pre-select which residues to subject to these more involved calculations involving inter-residue couplings. However, in principle, such calculations can be applied to any residues with nearby protonatable neighbours. Our formalism ensures that if alchemical calculations suggest no coupling, the final pK a estimate will remain similar to that of a standard calculation without coupling considerations.