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How protein thermodynamics and folding mechanisms are altered by the chaperonin cage: Molecular simulations

By Fumiko Takagi, Nobuyasu Koga and Shoji Takada

Abstract

How the Escherichia coli GroEL/ES chaperonin assists folding of a substrate protein remains to be uncovered. Recently, it was suggested that confinement into the chaperonin cage itself can significantly accelerate folding of a substrate. Performing comprehensive molecular simulations of eight proteins confined into various sizes L of chaperonin-like cage, we explore how and to what extent protein thermodynamics and folding mechanisms are altered by the cage. We show that a substrate protein is remarkably stabilized by confinement; the estimated increase in denaturation temperature ΔT(f) is as large as ≈60°C. For a protein of size R(0), the stabilization ΔT(f) scales as (R(0)/L)(ν), where ν ≈ 3, which is consistent with a mean field theory of polymer. We also found significant free energy cost of confining a protein, which increases with R(0)/L, indicating that the confinement requires external work provided by the chaperonin system. In kinetic study, we show the folding is accelerated in a modestly well confined case, which is consistent with a recent experimental result on ribulose-1,5-bisphosphate carboxylase-oxygenase folding and simulation results of a β hairpin. Interestingly, the acceleration of folding is likely to be larger for a protein with more complex topology, as quantified by the contact order. We also show how ensemble of folding pathways are altered by the chaperonin-like cage calculating a variant of φ value used in the study of spontaneous folding

Topics: Biological Sciences
Publisher: National Academy of Sciences
Year: 2003
DOI identifier: 10.1073/pnas.1831920100
OAI identifier: oai:pubmedcentral.nih.gov:208763
Provided by: PubMed Central
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