Cooperative Folding Kinetics of BBL Protein and Peripheral Subunit-Binding Domain Homologues

Recent experiments claiming that Naf-BBL protein follows a global downhill folding raised an important controversy as to the folding mechanism of fast-folding proteins. Under the global downhill folding scenario, not only do proteins undergo a gradual folding, but folding events along the continuous folding pathway also could be mapped out from the equilibrium denaturation experiment. Based on the exact calculation using a free energy landscape, relaxation eigenmodes from a master equation, and Monte-Carlo simulation of an extended Munoz-Eaton model that incorporates multiscale-heterogeneous pairwise interactions between amino acids, here we show (1) that the very nature of a two-state cooperative transition such as a bimodal distribution from an exact free energy landscape and biphasic relaxation kinetics manifest in the thermodynamics and folding-unfolding kinetics of BBL and peripheral subunit-binding domain homologues. Our results provide an unequivocal resolution to the fundamental controversy related to the global downhill folding scheme, whose applicability to other proteins should be critically reexamined.(1) Proc. Nat'l. Acad. Sci. (USA), Vol.105, 2397-2402 (2008).