Quantitative Effects of Substrate–Environment Interactions on the Free Energy Barriers of Reactions

Quantifying the effects of the intermolecular noncovalent interactions between substrates and reaction environments on the free energy barriers (FEBs) of both enzymatic and solution reactions is vital for understanding the origin of the enormous catalytic power of enzymes. However, such a task is difficult to accomplish. Using a theoretical derivation approach and experimental validations, we established models to quantify the effects of intermolecular noncovalent interactions on the FEBs of both enzymatic and solution reactions. We found that noncovalent interactions similarly affect the FEBs of enzymatic and solution reactions. We also found that the noncovalent interactions of the substrate atoms undergoing a charge density alteration largely affect the FEBs of reactions. These effects strongly correlate with the H-bonding capabilities of the environmental atoms of the noncovalent interactions. The proposed models make it possible to quantify the catalytic power contributed by substrate–environment interactions and provide guidance for the catalysis of reactions by altering the H-bonding capabilities of the environmental atoms. This study may facilitate enzyme engineering and provide a novel approach for exploring the catalysis of both enzymatic and solution reactions.