Here, ∆∆G 0 corresponds to ∆∆G env : the free energy of deprotonating residue A while in the presence of protonated B. Similarly, ∆∆G 3 corresponds to the deprotonation of A in the presence of deprotonated B. In both cases, the remaining protonatable sites in the protein are fixed to their model states at pH 7.4 (i.e., Asp/Glu: deprotonated, Lys/Cys: protonated). We also have ∆∆G 1 and ∆∆G 2 , which will shift the populations of "reactants" and "products" with