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J. Biol. Chem., Vol. 279, Issue 18, 19046-19050, April 30, 2004

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On Evolutionary Conservation of Thermodynamic Coupling in Proteins^*

Anthony A. Fodor and Richard W. Aldrich

From the Department of Molecular and Cellular Physiology, and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5345

The inherent complexity of thermodynamic coupling in proteins presents a major challenge in understanding and engineering protein function. Recent work has argued that the study of proteins can be simplified by the use of correlated mutations in the evolutionary record to locate a small subset of thermodynamically coupled residues that participate in functionally important, evolutionarily conserved energetic pathways. To test this hypothesis, we examined the predictions of correlated mutation algorithms for a number of proteins for which coupling between residues has been determined by analysis of double mutant cycles. We find that correlated mutation algorithms can find residue pairs that are physically close and that physically close residue pairs tend to be thermodynamically coupled. We find little evidence, however, for the hypothesis that thermodynamic coupling is limited to the subset of evolutionarily constrained residue positions.

Received for publication, March 8, 2004

^* This work was supported by the Mathers Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

An investigator with the Howard Hughes Medical Institute. To whom correspondence and requests for materials should be addressed: Dept. of Molecular and Cellular Physiology, and Howard Hughes Medical Inst., Stanford University School of Medicine, Beckman Center, 279 Campus Dr., Stanford, CA 94305-5345. Tel.: 650-723-6531; Fax: 650-725-4463; E-mail: raldrich{at}stanford.edu.

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