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Folding at the speed limit


Many small proteins seem to fold by a simple process explicable by conventional chemical kinetics and transition-state theory. This assumes an instant equilibrium between reactants and a high-energy activated state1. In reality, equilibration occurs on timescales dependent on the molecules involved, below which such analyses break down1. The molecular timescale, normally too short to be seen in experiments, can be of a significant length for proteins. To probe it directly, we studied very rapidly folding mutants of the five-helix bundle protein λ6–85, whose activated state is significantly populated during folding. A time-dependent rate coefficient below 2 µs signals the onset of the molecular timescale, and hence the ultimate speed limit for folding2. A simple model shows that the molecular timescale represents the natural pre-factor for transition state models of folding.

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Figure 1: Spectroscopy of mutant proteins.
Figure 2: Relaxation after temperature jumps.
Figure 3: Rate coefficient determination.
Figure 4: One-dimensional free-energy model used to reproduce the λQ33Y and λD14A data as a function of temperature.


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We thank T. Oas for suggesting many helpful lambda repressor mutations. This work was supported by an Alumni Scholarship and a Camille Dreyfus Teacher–Scholar Award to M.G.

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Correspondence to Martin Gruebele.

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Yang, W., Gruebele, M. Folding at the speed limit. Nature 423, 193–197 (2003).

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