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Protein Science (2005), 14:1643-1660. Published by Cold Spring Harbor Laboratory Press. Copyright © 2005 The Protein Society
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A critical assessment of the topomer search model of protein folding using a continuum explicit-chain model with extensive conformational sampling

Stefan Wallin and Hue Sun Chan

Department of Biochemistry and Department of Medical Genetics & Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

(RECEIVED December 16, 2004; FINAL REVISION February 23, 2005; ACCEPTED February 23, 2005)

Recently, a series of closely related theoretical constructs termed the "topomer search model" (TSM) has been proposed for the folding mechanism of small, single-domain proteins. A basic assumption of the proposed scenarios is that the rate-limiting step in folding is an essentially unbiased, diffusive search for a conformational state called the native topomer defined by an overall native-like topological pattern. Successes in correlating TSM-predicted folding rates with that of real proteins have been interpreted as experimental support for the model. To better delineate the physics entailed, key TSM concepts are examined here using extensive Langevin dynamics simulations of continuum C{alpha} chain models. The theoretical native topomers of four experimentally well-studied two-state proteins are characterized. Consistent with the TSM perspective, we found that the sizes of the native topomers increase with experimental folding rate. However, a careful determination of the corresponding probabilities that the native topomers are populated during a random search fails to reproduce the previously predicted folding rates. Instead, our results indicate that an unbiased TSM search for the native topomer amounts to a Levinthal-like process that would take an impossibly long average time to complete. Furthermore, intraprotein contacts in all four native topomers considered exhibit no apparent correlation with the experimental {phi}-values determined from the folding kinetics of these proteins. Thus, the present findings suggest that certain basic, generic yet essential energetic features in protein folding are not accounted for by TSM scenarios to date.

Keywords: protein folding; topomer search model; topomer-sampling model; Levinthal search; explicit-chain modeling

Article and publication are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041317705.

Reprint requests to: Hue Sun Chan, Department of Biochemistry, University of Toronto, 1 King’s College Circle, Toronto, Ontario M5S 1A8, Canada; e-mail: chan{at}arrhenius.med.utoronto.ca; fax: 1-416- 978-8548.


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