Cooperative folding kinetics of BBL protein and peripheral subunit-binding domain homologues

doi:10.1073/pnas.0708480105

Cooperative folding kinetics of BBL protein and peripheral subunit-binding domain homologues

*National Research Laboratory for Computational Proteomics and Biophysics, Department of Physics, Pusan National University, Busan 609-735, Korea;
^‡Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, United Kingdom;
^¶Molecular Cancer Research Center, Korea Research Institute for Bioscience and Biotechnology, Daejeon 305-806, Korea; and
^‖Department of Chemistry, Sookmyoung Women's University, Seoul 140-742, Korea

Edited by Alan R. Fersht, University of Cambridge, Cambridge, United Kingdom, and approved December 21, 2007 (received for review September 7, 2007)

Abstract

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 Muñoz–Eaton model that incorporates multiscale-heterogeneous pairwise interactions between amino acids, here we show 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.

Footnotes

**To whom correspondence should be addressed. E-mail: chang{at}random.phys.pusan.ac.kr
Author contributions: I.C. designed research; W.Y., K.C., M.C., M.H., and I.C. performed research; K.-H.H., S.H., and I.C. contributed new reagents/analytic tools; W.Y., K.C., M.C., M.H., K.-H.H., S.H., and I.C. analyzed data; and I.C. wrote the paper.
↵ ^†Present address: Ministry of Science and Technology, Gwacheon 427-715, Korea.
↵ ^§Present address: Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708480105/DC1.