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Proc Natl Acad Sci U S A. 2005 Apr 5;102(14):5026-31. Epub 2005 Mar 25.

A protein folding pathway with multiple folding intermediates at atomic resolution.

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  • 1Laboratory of Biochemistry, National Cancer Institute, National Institutes of Health, Building 37, Room 6114E, Bethesda, MD 20892, USA.


Using native-state hydrogen-exchange-directed protein engineering and multidimensional NMR, we determined the high-resolution structure (rms deviation, 1.1 angstroms) for an intermediate of the four-helix bundle protein: Rd-apocytochrome b562. The intermediate has the N-terminal helix and a part of the C-terminal helix unfolded. In earlier studies, we also solved the structures of two other folding intermediates for the same protein: one with the N-terminal helix alone unfolded and the other with a reorganized hydrophobic core. Together, these structures provide a description of a protein folding pathway with multiple intermediates at atomic resolution. The two general features for the intermediates are (i) native-like backbone topology and (ii) nonnative side-chain interactions. These results have implications for important issues in protein folding studies, including large-scale conformation search, -value analysis, and computer simulations.

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