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BIOLOGICAL SCIENCES / BIOPHYSICS
Functional residues serve a dominant role in mediating the cooperativity of the protein ensemble
Department of Biochemistry and Molecular Biology, and Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555-1068
Edited by José N. Onuchic, University of California at San Diego, La Jolla, CA, and approved January 23, 2007 (received for review August 16, 2006)
Conformational fluctuations in proteins have emerged as a potentially important aspect of biological function, although the precise relationship and the implications have yet to be fully explored. Numerous studies have reported that the binding of ligand can influence fluctuations. However, the role of the binding site in mediating these fluctuations is not known. Of particular interest is whether in addition to serving as structural scaffolds for recognition and catalysis, active-site residues may also play a role in modulating the cooperative network. To address this question, we employ an experimentally validated ensemble-based description of proteins to elucidate the extent to which perturbations at different sites can influence the cooperative network in the protein. Applying this method to a database of test proteins, it is found statistically that binding sites are located in regions most able to affect the cooperative network, even for cooperative interactions between residues distant to the binding sites. This indicates that the conformational manifold under native conditions is determined by the network of cooperative interactions within the protein and suggests that proteins have evolved to use these conformational fluctuations in carrying out their functions. Furthermore, because the energetic coupling pattern calculated for each protein is robust and relatively insensitive to sequence, these studies further suggest that binding sites evolved in regions of the protein that are inherently poised to take advantage of the fluctuations in the native structure.
COREX analysis | energetic coupling | native state ensemble | thermodynamic linkage
The authors declare no conflict of interest.
This article is a PNAS direct submission.
*To whom correspondence should be addressed. E-mail: vjhilser{at}utmb.edu
© 2007 by The National Academy of Sciences of the USA
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