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Published December 10, 1996 | Published
Journal Article Open

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


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.

Additional Information

© 1996 The National Academy of Sciences of the USA. Communicated by John I. Brauman, Stanford University, Stanford, CA, September 9, 1996 (received for review June 14, 1996). We thank J. Brauman, W. Cleland, M. Kreevoy, and A. Williams for discussions; the Bordwell group for technical help; and P. Frey for permission to cite unpublished work. This work was supported by grants from the Lucille P. Markey Charitable Trust and the Chicago Community Trust to D.H. D.H. is a Lucille P. Markey Scholar and a Searle Scholar. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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