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

摘要

Simulations of first-passage folding of the antiparallel β-sheet miniprotein beta3s, which has been intensively studied under equilibrium conditions by A. Caflisch and co-workers, show that the kinetics and dynamics are significantly different from those for equilibrium folding. Because the folding of a protein in a living system generally corresponds to the former (i.e., the folded protein is stable and unfolding is a rare event), the difference is of interest. In contrast to equilibrium folding, the Ch-curl conformations become very rare because they contain unfavorable parallel β-strand arrangements, which are difficult to form dynamically due to the distant N- and C-terminal strands. At the same time, the formation of helical conformations becomes much easier (particularly in the early stage of folding) due to short-range contacts. The hydrodynamic descriptions of the folding reaction have also revealed that while the equilibrium flow field presented a collection of local vortices with closed ”streamlines”, the first-passage folding 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.