How Enzymes Work: Analysis by Modern Rate Theory and Computer Simulations

Author:

Garcia-Viloca Mireia12,Gao Jiali12,Karplus Martin12,Truhlar Donald G.12

Affiliation:

1. Department of Chemistry and Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA.

2. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA02138, USA, and Laboratoire de Chimie Biophysique ISIS, Université Louis Pasteur, 67000 Strasbourg, France.

Abstract

Advances in transition state theory and computer simulations are providing new insights into the sources of enzyme catalysis. Both lowering of the activation free energy and changes in the generalized transmission coefficient (recrossing of the transition state, tunneling, and nonequilibrium contributions) can play a role. A framework for understanding these effects is presented, and the contributions of the different factors, as illustrated by specific enzymes, are identified and quantified by computer simulations. The resulting understanding of enzyme catalysis is used to comment on alternative proposals of how enzymes work.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Reference131 articles.

1. The Depth of Chemical Time and the Power of Enzymes as Catalysts

2. L. Pauling, Chem. Eng. News24, 1375 (1946).

3. R. L. Schowen, in Transition States of Biochemical Processes, R. D. Gandour, R. L. Schowen, Eds. (Plenum, New York, 1978), p. 77.

4. Ahistorical overview of mechanistic enzymology which serves as an excellent complement to the present analysis was published recently by Bugg ( 124 ). He points out that many enzymologists continue to search for the “elusive additional mechanisms by which enzymes may achieve high rates of catalysis” (p. 488). The thesis of the present article is that modern simulations of transition states are a powerful tool for discovering these mechanisms and that all such mechanisms can be understood in terms of various contributions to Eq. 1a. In another complementary article published after the present review was submitted Benkovic and Hammes-Schiffer ( 125 ) provide a perspective on the contributions to catalysis by focusing on the properties of DHFR.

5. H. Eyring, A. E. Stern, Chem. Rev.24, 2 (1939).

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