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Side chain burial and hydrophobic core packing in protein folding transition states

Department of Chemistry, McGill University, Montreal H3A 2K6, Canada

(RECEIVED July 3, 2007; FINAL REVISION July 3, 2007; ACCEPTED December 28, 2007)

A critical step in the folding pathway of globular proteins is the formation of a tightly packed hydrophobic core. Several mutational studies have addressed the question of whether tight packing interactions are present during the rate-limiting step of folding. In some of these investigations, substituted side chains have been assumed to form native-like interactions in the transition state when the folding rates of mutant proteins correlate with their native-state stabilities. Alternatively, it has been argued that side chains participate in nonspecific hydrophobic collapse when the folding rates of mutant proteins correlate with side-chain hydrophobicity. In a reanalysis of published data, we have found that folding rates often correlate similarly well, or poorly, with both native-state stability and side-chain hydrophobicity, and it is therefore not possible to select an appropriate transition state model based on these one-parameter correlations. We show that this ambiguity can be resolved using a two-parameter model in which side chain burial and the formation of all other native-like interactions can occur asynchronously. Notably, the model agrees well with experimental data, even for positions where the one-parameter correlations are poor. We find that many side chains experience a previously unrecognized type of transition state environment in which specific, native-like interactions are formed, but hydrophobic burial dominates. Implications of these results to the design and analysis of protein folding studies are discussed.

Keywords: protein folding; phi value analysis; hydrophobic core; hydrophobicity; side chain packing; mutagenesis

Reprint requests to: Anthony Mittermaier, Department of Chemistry, McGill University, 801 Sherbrooke Street West, Room 322, Montreal H3A 2K6, Canada; e-mail: anthony.mittermaier{at}mcgill.ca; fax: (514) 398-3797.

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.073105408.

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