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First Passage Analysis of the Folding of a β-SheetMiniprotein: Is it More Realistic Than the Standard Equilibrium Approach?

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Title: First Passage Analysis of the Folding of a β-SheetMiniprotein: Is it More Realistic Than the Standard Equilibrium Approach?
Authors: Kalgin, Igor V.1, Chekmarev, Sergei F.1, Karplus, Martin1
Source: Journal of Physical Chemistry B. Apr2014, Vol. 118 Issue 16, p4287-4299. 13p.
Subjects: Protein folding -- Computer simulation, Hydrodynamics, Chemical equilibrium, Chemical kinetics, Protein conformation, Hydrogen bonding
Abstract: Simulations of first-passage foldingof the antiparallel β-sheetminiprotein beta3s, which has been intensively studied under equilibriumconditions by A. Caflisch and co-workers, show that the kinetics anddynamics are significantly different from those for equilibrium folding.Because the folding of a protein in a living system generally correspondsto the former (i.e., the folded protein is stable and unfolding isa rare event), the difference is of interest. In contrast to equilibriumfolding, the Ch-curl conformations become very rare because they containunfavorable parallel β-strand arrangements, which are difficultto form dynamically due to the distant N- and C-terminal strands.At the same time, the formation of helical conformations becomes mucheasier (particularly in the early stage of folding) due to short-rangecontacts. The hydrodynamic descriptions of the folding reaction havealso revealed that while the equilibrium flow field presented a collectionof local vortices with closed ”streamlines”, the first-passagefolding is characterized by a pronounced overall flow from the unfoldedstates to the native state. The flows through the locally stable structuresCs-or and Ns-or, which are conformationally close to the native state,are negligible due to detailed balance established between these structuresand the native state. Although there are significant differences inthe general picture of the folding process from the equilibrium andfirst-passage folding simulations, some aspects of the two are inagreement. The rate of transitions between the clusters of characteristicprotein conformations in both cases decreases approximately exponentiallywith the distance between the clusters in the hydrogen bond distancespace of collective variables, and the folding time distribution inthe first-passage segments of the equilibrium trajectory is in goodagreement with that for the first-passage folding simulations. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
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Abstract:Simulations of first-passage foldingof the antiparallel β-sheetminiprotein beta3s, which has been intensively studied under equilibriumconditions by A. Caflisch and co-workers, show that the kinetics anddynamics are significantly different from those for equilibrium folding.Because the folding of a protein in a living system generally correspondsto the former (i.e., the folded protein is stable and unfolding isa rare event), the difference is of interest. In contrast to equilibriumfolding, the Ch-curl conformations become very rare because they containunfavorable parallel β-strand arrangements, which are difficultto form dynamically due to the distant N- and C-terminal strands.At the same time, the formation of helical conformations becomes mucheasier (particularly in the early stage of folding) due to short-rangecontacts. The hydrodynamic descriptions of the folding reaction havealso revealed that while the equilibrium flow field presented a collectionof local vortices with closed ”streamlines”, the first-passagefolding is characterized by a pronounced overall flow from the unfoldedstates to the native state. The flows through the locally stable structuresCs-or and Ns-or, which are conformationally close to the native state,are negligible due to detailed balance established between these structuresand the native state. Although there are significant differences inthe general picture of the folding process from the equilibrium andfirst-passage folding simulations, some aspects of the two are inagreement. The rate of transitions between the clusters of characteristicprotein conformations in both cases decreases approximately exponentiallywith the distance between the clusters in the hydrogen bond distancespace of collective variables, and the folding time distribution inthe first-passage segments of the equilibrium trajectory is in goodagreement with that for the first-passage folding simulations. [ABSTRACT FROM AUTHOR]
ISSN:15206106
DOI:10.1021/jp412729r