Side chain burial and hydrophobic core packing in protein folding transition states.
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.
Farber
Patrick J
PJ
Department of Chemistry, McGill University, Montreal H3A 2K6, Canada.
Mittermaier
Anthony
A
D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008958:Models, Molecular; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D051076:Proto-Oncogene Proteins c-fyn / Q000737:chemistry; D012269:Ribosomal Proteins / Q000737:chemistry; D013816:Thermodynamics
D011506:Proteins; D012269:Ribosomal Proteins; C049650:ribosomal protein L9; D051076:Proto-Oncogene Proteins c-fyn