TY - JOUR
T1 - Protein folding funnels
T2 - The nature of the transition state ensemble
AU - Onuchic, José Nelson
AU - Socci, Nicholas D.
AU - Luthey-Schulten, Zaida
AU - Wolynes, Peter G.
N1 - Funding Information:
We thank Eric Boczko and Charles Brooks for sharing with us their unpublished simulation data and A Fersht, H Roder and W Eaton for critically reading the manuscript. ND Socci is a Chancellor's Fellow at UCSD. The work at UCSD was supported by NSF (Grant no. MCB-93-16186) and at Illinois through NIH (Grant no. 2 R01 GM44557).
PY - 1996
Y1 - 1996
N2 - Background: Energy landscape theory predicts that the folding funnel for a small fast-folding α-helical protein will have a transition state half-way to the native state. Estimates of the position of the transition state along an appropriate reaction coordinate can be obtained from linear free energy relationships observed for folding and unfolding rate constants as a function of denaturant concentration. The experimental results of Huang and Oas for λ repressor, Fersht and collaborators for CI2, and Gray and collaborators for cytochrome c indicate a free energy barrier midway between the folded and unfolded regions. This barrier arises from an entropic bottleneck for the folding process. Results: In keeping with the experimental results, lattice simulations based on the folding funnel description show that the transition state is not just a single conformation, but rather an ensemble of a relatively large number of configurations that can be described by specific values of one or a few order parameters (e.g. the fraction of native contacts). Analysis of this transition state or bottleneck region from our lattice simulations and from atomistic models for small α-helical proteins by Boczko and Brooks indicates a broad distribution for native contact participation in the transition state ensemble centered around 50%. Importantly, however, the lattice-simulated transition state ensemble does include some particularly hot contacts, as seen in the experiments, which have been termed by others a folding nucleus. Conclusions: Linear free energy relations provide a crude spectroscopy of the transition state, allowing us to infer the values of a reaction coordinate based on the fraction of native contacts. This bottleneck may be thought of as a collection of delocalized nuclei where different native contacts will have different degrees of participation. The agreement between the experimental results and the theoretical predictions provides strong support for the landscape analysis.
AB - Background: Energy landscape theory predicts that the folding funnel for a small fast-folding α-helical protein will have a transition state half-way to the native state. Estimates of the position of the transition state along an appropriate reaction coordinate can be obtained from linear free energy relationships observed for folding and unfolding rate constants as a function of denaturant concentration. The experimental results of Huang and Oas for λ repressor, Fersht and collaborators for CI2, and Gray and collaborators for cytochrome c indicate a free energy barrier midway between the folded and unfolded regions. This barrier arises from an entropic bottleneck for the folding process. Results: In keeping with the experimental results, lattice simulations based on the folding funnel description show that the transition state is not just a single conformation, but rather an ensemble of a relatively large number of configurations that can be described by specific values of one or a few order parameters (e.g. the fraction of native contacts). Analysis of this transition state or bottleneck region from our lattice simulations and from atomistic models for small α-helical proteins by Boczko and Brooks indicates a broad distribution for native contact participation in the transition state ensemble centered around 50%. Importantly, however, the lattice-simulated transition state ensemble does include some particularly hot contacts, as seen in the experiments, which have been termed by others a folding nucleus. Conclusions: Linear free energy relations provide a crude spectroscopy of the transition state, allowing us to infer the values of a reaction coordinate based on the fraction of native contacts. This bottleneck may be thought of as a collection of delocalized nuclei where different native contacts will have different degrees of participation. The agreement between the experimental results and the theoretical predictions provides strong support for the landscape analysis.
KW - Delocalized nucleus
KW - Denaturant lattice simulations
KW - Linear free energy relations
KW - Protein folding funnel
KW - Transition state ensemble
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U2 - 10.1016/S1359-0278(96)00060-0
DO - 10.1016/S1359-0278(96)00060-0
M3 - Article
C2 - 9080190
AN - SCOPUS:0030322669
VL - 1
SP - 441
EP - 450
JO - Folding and Design
JF - Folding and Design
SN - 1359-0278
IS - 6
ER -