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Molecular collapse: the rate-limiting step in two-state cytochrome c folding
T R Sosnick1, L Mayne, S W Englander
1The Johnson Research Foundation, Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia 19104-6059, USA.
Proteins
|April 1, 1996
Summary
Protein folding, specifically cytochrome c (cyt c) molecular collapse, is a slow, barrier-crossing process, not an easy downhill path. This initial collapse, limited by finding a transition state, dictates the overall folding speed.
Area of Science:
- Biochemistry and Molecular Biology
- Protein Dynamics and Folding
Background:
- The common assumption of protein folding as a simple, downhill energy process is challenged.
- Cytochrome c (cyt c) folding kinetics were investigated to understand early folding events.
Purpose of the Study:
- To elucidate the nature of the initial molecular collapse in cytochrome c folding.
- To determine the rate-limiting step and key barriers in the cyt c folding pathway.
Main Methods:
- Experimental investigation of cytochrome c folding dynamics.
- Analysis of the initial molecular collapse as a barrier-crossing process.
Main Results:
- The initial molecular collapse of cyt c is a time-consuming, cooperative barrier-crossing event, not energetically downhill.
- This collapse process is limited by an uphill search for a transition state structure, dictating millisecond folding times.
- A 'burst phase' at native conditions is a non-specific response to denaturant reduction.
Conclusions:
- The rate-limiting step in cyt c folding is the initial molecular collapse and nucleation event.
- Subsequent folding proceeds rapidly through metastable intermediates to the native state.
- Understanding these initial barriers is crucial for comprehending protein folding mechanisms.