Applying a linear projection to understand patterns in catalytic activity raises a highly relevant question: how linear are the effects of functional group substitutions? To address this, we generated all possible pairs of functional group substitutions for catalysts B and C, then calculated their O2 binding energies. For C, we chose to perform calculations only on the C-1 active site. We computed the difference between the O2 binding energy of the doubly substituted catalysts and the corresponding unsubstituted B or C-1. We also calculated the sum of the binding energy difference for the two singly substituted catalysts with substitutions that correspond to those in the doubly substituted catalysts, and plotted the correlation between the effect of the double substitutions and the sum effect of the individual substitutions on different catalysts (Figure ). The sum effect of the two single substitutions is a good predictor of the effect of double substitutions, especially so for catalyst B and to moderate extent for C-1. The diminished correlation for C-1 may be a result of larger perturbations being less linear in these systems in general, or a sensitivity of catalyst C to multiple substitutions that is not captured by single substitutions. These results indicate that these GCCs may be tuned with multiple functional group substitutions, and that as long as no modifications are made directly to the active site the effects of the substitutions can be predicted relatively reliably using only information about the effects of single substitutions.