Fast protein folding kinetics - PubMed (original) (raw)

Fast protein folding kinetics

Jack Schonbrun et al. Proc Natl Acad Sci U S A. 2003.

Abstract

Proteins are complex molecules, yet their folding kinetics is often fast (microseconds) and simple, involving only a single exponential function of time (called two-state kinetics). The main model for two-state kinetics has been transition-state theory, where an energy barrier defines a slow step to reach an improbable structure. But how can barriers explain fast processes, such as folding? We study a simple model with rigorous kinetics that explains the high speed instead as a result of the microscopic parallelization of folding trajectories. The single exponential results from a separation of timescales; the parallelization of routes is high at the start of folding and low thereafter. The ensemble of rate-limiting chain conformations is different from in transition-state theory; it is broad, overlaps with the denatured state, is not aligned along a single reaction coordinate, and involves well populated, rather than improbable, structures.

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Figures

Fig. 1.

(a) Transition-state explanation of single-exponential processes, such as protein folding, involves a rate-limiting step, shown as an obligatory thermodynamic barrier. (b) Theory and simulations show that energy landscapes for protein folding are funnel-shaped and have no apparent microscopic energetic or entropic barriers.

Fig. 2.

Series vs. parallel models of kinetics. (Right) When microscopic steps are in series, the macroscopic flux is limited by the microscopic bottleneck rate. The hypothetical numbers illustrate the fluxes through different microscopic steps. (Left) But if parallel microscopic routes exist, the macroscopic flux is greater than the largest microscopic flux.

Fig. 3.

The rate of folding is faster than almost all the microscopic transitions between conformations, supporting the parallel model. The large arrow shows the overall folding rate. The histogram to the right shows the distribution of microscopic transition fluxes. The small arrows on the left show the level-to-level transition rates between energy levels: 0–1 indicates transitions at the top of the energy funnel, 1–2 is the next level down, etc. The level-to-level fluxes are high because many microroutes contribute to them.

Fig. 4.

(Left) The transition-state model involves macrostates (R, reactant; TS, transition state; P, product) that are small, localized ensembles of microstates. Each microscopic structure is a member of only one macrostate. (Right) The present model shows that the macrostates for two-state protein folding (D), the denatured state, or TS, the transition state under folding conditions) are broad ensembles that encompass all the nonnative chain conformations. A given chain conformation is not a unique member of only one macrostate.

Fig. 5.

(a) Chevron plot showing predicted relaxation rate (k = _k_f + _k_u) versus strength of native contacts. The histograms show the distribution of conformations (most native-like to the left) under different folding conditions for the denatured ensemble _D_f (b) and the apparent transition state _TS_f (c). Under increasingly native-like conditions, both ensembles _D_f and _TS_f become more native-like. Hence, the left (folding branch) of the chevron curve shows rollover, a deviation from linearity. Under strong native conditions, the _D_f ensemble is more native-like than the _TS_f ensemble.

References

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Fast protein folding kinetics - PubMed (original) (raw)