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Behind the folding funnel diagram

A Corrigendum to this article was published on 17 August 2011

This article has been updated

This Commentary clarifies the meaning of the funnel diagram, which has been widely cited in papers on protein folding. To aid in the analysis of the funnel diagram, this Commentary reviews historical approaches to understanding the mechanism of protein folding. The primary role of free energy in protein folding is discussed, and it is pointed out that the decrease in the configurational entropy as the native state is approached hinders folding, rather than guiding it. Diagrams are introduced that provide a less ambiguous representation of the factors governing the protein folding reaction than the funnel diagram.

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Figure 1: A schematic folding funnel diagram.
Figure 2: Folding of a lattice polymer.
Figure 3: Folding of a designed α-helical peptide.
Figure 4: Arrhenius plots for folding reaction.

Change history

  • 14 July 2011

    In the version of this article initially published, there was an error in the abstract that stated an increase in the configurational entropy hinders folding, but it should read that there is a decrease in the configurational entropy that hinders folding. The error has been corrected in the HTML and PDF versions of the article.


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I thank A. Caflisch, A. Dinner and B. Qi for providing results and comments on the manuscript and M. Cecchini and V. Ovchinnikov for comments on the manuscript and help with the figures. Owing to space limitation, some original citations have been omitted; many can be found in reference 1 or reference 7. The work done at Harvard was supported, in part, by a grant from the US National Institutes of Health.

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Correspondence to Martin Karplus.

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Karplus, M. Behind the folding funnel diagram. Nat Chem Biol 7, 401–404 (2011).

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