Nonadditive interactions in protein folding: the zipper model of cytochrome C.

Hydrogen exchange experiments (Krishna et al. in J. Mol. Biol. 359:1410, 2006) reveal that folding-unfolding of cytochrome c occurs along a defined pathway in a sequential, stepwise manner. The simplified zipper-like model involving nonadditive coupling is proposed to describe the classical "on pathway" folding-unfolding behavior of cytochrome c. Using free energy factors extracted from HX experiments, the model can predict and explain cytochrome c behavior in spectroscopy studies looking at folding equilibria and kinetics. The implications of the proposed model are discussed for such problems as classical pathway vs. energy landscape conceptions, structure and function of a native fold, and interplay of secondary and tertiary interactions.