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Chevron Behavior and Isostable Enthalpic Barriers in Protein Folding: Successes and Limitations of Simple G-like Modeling

Protein Engineering Network of Centres of Excellence, Department of Biochemistry, and Department of Medical Genetics & Microbiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

Correspondence: Address reprint requests to Hue Sun Chan, Dept. of Biochemistry, University of Toronto, Medical Sciences Building, 5th Floor, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel.: 416-978-2697; Fax: 416-978-8548; E-mail: chan{at}arrhenius.med.toronto.edu.

It has been demonstrated that a "near-Levinthal" cooperative mechanism, whereby the common G interaction scheme is augmented by an extra favorability for the native state as a whole, can lead to apparent two-state folding/unfolding kinetics over a broad range of native stabilities in lattice models of proteins. Here such a mechanism is shown to be generalizable to a simplified continuum (off-lattice) Langevin dynamics model with a C protein chain representation, with the resulting chevron plots exhibiting an extended quasilinear regime reminiscent of that of apparent two-state real proteins. Similarly high degrees of cooperativity are possible in G-like continuum models with rudimentary pairwise desolvation barriers as well. In these models, cooperativity increases with increasing desolvation barrier height, suggesting strongly that two-state-like folding/unfolding kinetics would be achievable when the pairwise desolvation barrier becomes sufficiently high. Besides cooperativity, another generic folding property of interest that has emerged from published experiments on several apparent two-state proteins is that their folding relaxation under constant native stability (isostability) conditions is essentially Arrhenius, entailing high intrinsic enthalpic folding barriers of 17–30 kcal/mol. Based on a new analysis of published data on barnase, here we propose that a similar property should also apply to a certain class of non-two-state proteins that fold with chevron rollovers. However, several continuum G-like constructs considered here fail to predict any significant intrinsic enthalpic folding barrier under isostability conditions; thus the physical origin of such barriers in real proteins remains to be elucidated.

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