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Molecular collapse: The rate‐limiting step in two‐state cytochrome c folding
Author(s) -
Sosnick Tobin R.,
Mayne Leland,
Englander S. Water
Publication year - 1996
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/(sici)1097-0134(199604)24:4<413::aid-prot1>3.0.co;2-f
Subject(s) - metastability , folding funnel , limiting , folding (dsp implementation) , protein folding , nucleation , contact order , phi value analysis , chemical physics , crystallography , downhill folding , intermediate state , chemistry , sequence (biology) , native state , physics , biophysics , thermodynamics , biology , biochemistry , atomic physics , mechanical engineering , electrical engineering , organic chemistry , engineering
Experiments with cytochrome c (cyt c) show that an initial folding event, molecular collapse, is not an energetically downhill continuum as commonly presumed but represents a large‐scale, time‐consuming, cooperative barrier‐crossing process. In the absence of later misfold‐reorganization barriers, the early collapse barrier limits cyt c folding to a time scale of milliseconds. The collapse process itself appears to be limited by an uphill search for some coarsely determined transition state structure that can nucleate subsequent energetically downhill folding events. An earlier “burst phase” event at strongly native conditions appears to be a non‐specific response of the unfolded chain to reduced denaturant concentration. The molecular collapse process may or may not require the co‐formation of the amino‐ and carboxyl‐terminal helices, which are present in an initial metastable intermediate directly following the rate‐limiting collapse. After the collapse‐nucleation event, folding can proceed rapidly in an apparent two‐state manner, probably by way of a predetermined sequence of metastable intermediates that leads to the native protein structure (Bai et al., Science 269:192–197, 1995).