The change in hydrogen bond strength accompanying charge rearrangement: Implications for enzymatic catalysis

Abstract

The equilibrium for formation of the intramolecular hydrogen bond (K HB ) in a series of substituted salicylate monoanions was investigated as a function of ΔpK a , the difference between the pK a values of the hydrogen bond donor and acceptor, in both water and dimethyl sulfoxide. The dependence of log K HB upon ΔpK a is linear in both solvents, but is steeper in dimethyl sulfoxide (slope = 0.73) than in water (slope = 0.05). Thus, hydrogen bond strength can undergo substantially larger increases in nonaqueous media than aqueous solutions as the charge density on the donor or acceptor atom increases. These results support a general mechanism for enzymatic catalysis, in which hydrogen bonding to a substrate is strengthened as charge rearranges in going from the ground state to the transition state; the strengthening of the hydrogen bond would be greater in a nonaqueous enzymatic active site than in water, thus providing a rate enhancement for an enzymatic reaction relative to the solution reaction. We suggest that binding energy of an enzyme is used to fix the substrate in the low-dielectric active site, where the strengthening of the hydrogen bond in the course of a reaction is increased.