One such insight is the the buffering of a residue dyad which maintained the free energy of protonation near zero (e.g., DJ-1: C106-E18). In various protein contexts, tuning the local residue environment surrounding pairs or groups of titratable residues to create large buffer regions over which the ∆G of protonation is close to zero could make the binding of a substrate more than sufficient to significantly alter the (de)protonation of a residue and ultimately the enzymatic activity.