Abstract
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Principles of Cooperative and Noncooperative Protein Folding
Hue Sun Chan
Departments of Biochemistry, and of Molecular Genetics
University of Toronto, Toronto, Ontario M5S 1A8 CANADA
http://biochemistry.utoronto.ca/chan/bch.html
Many small single-domain proteins undergo cooperative, switch-like folding/unfolding transitions with very low populations of intermediate, i.e., partially folded, conformations. Contrary to widely held expectations, the experimental phenomenon of cooperative, two-state-like folding is not accounted for by common notions about driving forces for folding. I will highlight how protein chain models with pairwise additive interactions are insufficient to account for the folding cooperativity of natural proteins, and how models with nonadditive local-nonlocal coupling may rationalize cooperative folding rates that are well correlated with native topology. To understand protein structure and function in general, however, it is important to also realize that not all proteins fold cooperatively. Recent experiments indicated that some proteins may fold noncooperatively in a "downhill," one-state manner; and appreciable variations in folding cooperativity were detected among natural proteins with approximately forty residues. The latter observation suggested that the behaviors of those proteins are valuable for delineating the contributing factors to folding cooperativity. To explore the role of native topology in a protein's propensity to fold cooperatively, we compared folding/unfolding thermodynamics simulated using three classes of native-centric coarse-grained chain models with different interaction schemes. We found a robust, experimentally valid rank ordering of model folding cooperativity independent of the interaction schemes tested, arguing strongly that native topology places significant constraints on how cooperatively a protein can be physically designed to fold.

Background references
Chan, Shimizu and Kaya (2004) Methods Enzymol 380, 350-379
Knott and Chan (2006) Proteins 65, 373-391
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