How Water Exclusion Accelerates Reactions in Enzyme Active Sites and Supramolecular Cavitands

The mechanism by which enzymes dramatically accelerate reactions remains a scientific grand challenge. Several laboratories recently reported that reactions in low-density interfacial water are orders of magnitude faster than in bulk water in the absence of enzymes. These findings align with previous reports that aqueous reactions are similarly accelerated in the gas phase. This suggests that, if for no other reason, enzymes accelerate reactions by carrying them out in active sites that exclude intervening water. This suggestion is validated by the statistical mechanical scaled particle theory of liquids, which shows that reactions run much faster in low-density water by dispensing with the large entropy costs of expanding cavities to accommodate transition states in highly cohesive bulk water. This general phenomenon will accelerate all enzymatic reactions with accelerations reflecting the slowness of the reference reactions in bulk water rather than the specific stabilization of transition states in dry active sites. Catalysis in hydrophobic, nonfunctionalized supramolecular cavitands should operate via a similar mechanism.