Premium
The topomer search model: A simple, quantitative theory of two‐state protein folding kinetics
Author(s) -
Makarov Dmitrii E.,
Plaxco Kevin W.
Publication year - 2003
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.0220003
Subject(s) - downhill folding , protein folding , folding (dsp implementation) , energy landscape , kinetics , statistical physics , smoothness , exponential function , lattice protein , chemistry , physics , phi value analysis , thermodynamics , mathematics , mathematical analysis , classical mechanics , biochemistry , electrical engineering , engineering
Most small, single‐domain proteins fold with the uncomplicated, single‐exponential kinetics expected for diffusion on a smooth energy landscape. Despite this energetic smoothness, the folding rates of these two‐state proteins span a remarkable million‐fold range. Here, we review the evidence in favor of a simple, mechanistic description, the topomer search model, which quantitatively accounts for the broad scope of observed two‐state folding rates. The model, which stipulates that the search for those unfolded conformations with a grossly correct topology is the rate‐limiting step in folding, fits observed rates with a correlation coefficient of ∼0.9 using just two free parameters. The fitted values of these parameters, the pre‐exponential attempt frequency and a measure of the difficulty of ordering an unfolded chain, are consistent with previously reported experimental constraints. These results suggest that the topomer search process may dominate the relative barrier heights of two‐state protein‐folding reactions.