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Protein Science (2004), 13:1750-1766. Published by Cold Spring Harbor Laboratory Press. Copyright © 2004 The Protein Society
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The effects of nonnative interactions on protein folding rates: Theory and simulation

Cecilia Clementi1,2 and Steven S. Plotkin3

1 Department of Chemistry, and W.M. Keck Center for Computational and Structural Biology, Rice University, Houston, Texas 77005, USA
2 Structural and Computational Biology and Molecular Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA
3 Department of Physics and Astronomy, University of British Columbia, Vancouver, BC V6T1Z1, Canada

(RECEIVED December 17, 2003; FINAL REVISION March 22, 2004; ACCEPTED March 25, 2004)



Abstract

Proteins are minimally frustrated polymers. However, for realistic protein models, nonnative interactions must be taken into account. In this paper, we analyze the effect of nonnative interactions on the folding rate and on the folding free energy barrier. We present an analytic theory to account for the modification on the free energy landscape upon introduction of nonnative contacts, added as a perturbation to the strong native interactions driving folding. Our theory predicts a rate-enhancement regime at fixed temperature, under the introduction of weak, nonnative interactions. We have thoroughly tested this theoretical prediction with simulations of a coarse-grained protein model, by using an off-lattice C{alpha}model of the src-SH3 domain. The strong agreement between results from simulations and theory confirm the nontrivial result that a relatively small amount of nonnative interaction energy can actually assist the folding to the native structure.

Keywords: protein folding; frustration; free energy landscape; folding rate; minimalist model; molecular dynamics

Reprint requests to: Cecilia Clementi, Department of Chemistry, Rice University, 6100 Main Street, Houston, TX 77005, USA; e-mail: cecilia{at}rice.edu; fax: (713) 348-5155; or Steven S. Plotkin, Department of Physics and Astronomy, University of British Columbia, 6224 Agricultural Road, Vancouver, BC V6T1Z1, Canada; e-mail: steve{at}physics.ubc.ca; fax: (604) 822-5324.

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.03580104.

Supplemental material: see www.proteinscience.org


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