title: Fast-folding protein kinetics, hidden intermediates, and the sequential stabilization model.
abstract: Do two-state proteins fold by pathways or funnels? Native-state hydrogen exchange experiments show discrete nonnative structures in equilibrium with the native state. These could be called hidden intermediates (HI) because their populations are small at equilibrium, and they are not detected in kinetic experiments. HIs have been invoked as disproof of funnel models, because funnel pictures appear to indicate (1) no specific sequences of events in folding; (2) a continuum, rather than a discrete ladder, of structures; and (3) smooth landscapes. In the present study, we solve the exact dynamics of a simple model. We find, instead, that the present microscopic model is indeed consistent with HIs and transition states, but such states occur in parallel, rather than along the single pathway predicted by the sequential stabilization model. At the microscopic level, we observe a huge multiplicity of trajectories. But at the macroscopic level, we observe two pathways of specific sequences of events that are relatively traditional except that they are in parallel, so there is not a single reaction coordinate. Using singular value decomposition, we show an accurate representation of the shapes of the model energy landscapes. They are highly complex funnels.
authors.affiliation: Center for Computational Biology and Bioinformatics, and Department of Molecular Genetics and Biochemistry, School of Medicine, University of Pittsburgh, Pennsylvania 15213, USA.
authors.forename: S Banu
authors.initials: SB
authors.lastname: Ozkan
authors.forename: Ken A
authors.initials: KA
authors.lastname: Dill
authors.forename: Ivet
authors.initials: I
authors.lastname: Bahar
mesh_terms: D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008432:Mathematical Computing; D008956:Models, Chemical; D011336:Probability; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000737:chemistry*; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
chemical_list: D011506:Proteins