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Fast‐folding protein kinetics, hidden intermediates, and the sequential stabilization model
Author(s) -
Ozkan S. Banu,
Dill Ken A.,
Bahar Ivet
Publication year - 2002
Publication title -
protein science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.353
H-Index - 175
eISSN - 1469-896X
pISSN - 0961-8368
DOI - 10.1110/ps.0207102
Subject(s) - funnel , energy landscape , statistical physics , protein folding , physics , kinetic energy , reaction coordinate , folding (dsp implementation) , transition state , native state , multiplicity (mathematics) , biological system , chemical physics , chemistry , computational chemistry , crystallography , classical mechanics , mathematics , thermodynamics , geometry , biology , biochemistry , organic chemistry , nuclear magnetic resonance , electrical engineering , engineering , catalysis
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.