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

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 DeltaT(f) is as large as approximate to60degreesC. For a protein of size R-0, the stabilization DeltaT(f) scales as (R-0/L)(nu), where nu approximate to 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 beta 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 phi value used in the study of spontaneous folding.