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Behind the folding funnel diagram

Nature Chemical Biology volume 7, pages 401–404 (2011)Cite this article

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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.

References

  1. Dobson, C.M., Sali, A. & Karplus, M. Angew. Chem. Int. Edn. Engl. 37, 868–893 (1998).

    Article  Google Scholar 

  2. Wolynes, P.G., Onuchic, J.N. & Thirumalai, D. Science 267, 1619–1620 (1995).

    Article  CAS  Google Scholar 

  3. Levinthal, C. How to fold graciously. in Mossbauer Spectroscopy in Biological Systems, Proceedings of a Meeting held at Allerton House, Monticello, Illinois (Debrunner, P., Tsibris, J.C.M. & Münck, E., eds.) 22 (University of Illinois Press, Urbana, 1969).

    Google Scholar 

  4. Tsai, C.J., Kumor, S., Ma, B.Y. & Nussinov, R. Protein Sci. 8, 1181–1190 (1999).

    Article  CAS  Google Scholar 

  5. Ngo, J.T., Marks, J. & Karplus, M. Computational complexity, protein structure prediction, and the Levinthal paradox. in The Protein Folding Problem and Tertiary Structure Prediction. (Merz, K. Jr. & Le Grand, S., eds.), 435–508 (Birkhäuser, Boston, 1994).

    Google Scholar 

  6. Wetlaufer, D.B. Proc. Natl. Acad. Sci. USA 70, 697–701 (1973).

    Article  CAS  Google Scholar 

  7. Fersht, A. Structure and Mechanism in Protein Science: A guide to Enzyme Catalysis and Protein Folding (WH Freeman, 1999).

    Google Scholar 

  8. Karplus, M. & Weaver, D.L. Nature 260, 404–406 (1976).

    Article  CAS  Google Scholar 

  9. Harrison, S.C. & Durbin, R. Proc. Natl. Acad. Sci. USA 82, 4028–4030 (1985).

    Article  CAS  Google Scholar 

  10. Zwanzig, R., Szabo, A. & Bacghi, B. Proc. Natl. Acad. Sci. USA 89, 20–22 (1992).

    Article  CAS  Google Scholar 

  11. Dill, K.A. & Chan, H.S. Nat. Struct. Biol. 4, 10–19 (1997).

    Article  CAS  Google Scholar 

  12. Calosci, N. et al. Proc. Natl. Acad. Sci. USA 105, 19241–19246 (2008).

    Article  CAS  Google Scholar 

  13. Sali, A., Shakhnovich, E. & Karplus, M. Nature 369, 248–251 (1994).

    Article  CAS  Google Scholar 

  14. Kubelka, J., Henry, E.R., Cellmer, T., Hofrichter, J. & Eaton, W.A. Proc. Natl. Acad. Sci. USA 105, 18655–18662 (2008).

    Article  CAS  Google Scholar 

  15. Lammert, H., Schug, A. & Onuchic, J. Bioinformatics 77, 881–891 (2009).

    CAS  Google Scholar 

  16. Zagrovic, B. & Pande, V. J. Comput. Chem. 24, 1432–1436 (2003).

    Article  CAS  Google Scholar 

  17. Shaw, D.E. et al. Science 330, 341–346 (2010).

    Article  CAS  Google Scholar 

  18. Baldwin, R.L. Nature 369, 183–184 (1994).

    Article  CAS  Google Scholar 

  19. Cavalli, A., Haberthuer, U., Paci, E. & Caflish, A. Protein Sci. 12, 1801–1803 (2003).

    Article  CAS  Google Scholar 

  20. Eaton, W.A., Thompson, P.A., Chan, C.-K., Hagen, S.J. & Hofrichter, J. Structure 4, 1133–1139 (1996).

    Article  CAS  Google Scholar 

  21. Ferrara, P., Apotolakis, J. & Caflisch, A. J. Phys. Chem. B 104, 5000–5010 (2000).

    Article  CAS  Google Scholar 

  22. Karplus, M. J. Phys. Chem. B 104, 11–27 (2000).

    Article  CAS  Google Scholar 

  23. Müller-Plathe, F. Introduction. in Soft Matter Vol. 1, Polymer Melts and Mixtures (Gompper, G. & Schick, M., eds.) (Wiley, 2006).

    Google Scholar 

  24. Onuchic, J.N., Socci, N.D., Luthey-Schulten, Z. & Wolynes, P.G. Fold. Des. 1, 441–450 (1996).

    Article  CAS  Google Scholar 

  25. Krivov, S.V., Muff, S., Caflisch, A. & Karplus, M. J. Phys. Chem. B 112, 8701–8714 (2008).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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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  1. Martin Karplus is in the Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts, USA and in the Laboratoire de Chimie Biophysique, Institut de Science et d'Ingénierie Supramoléculaires, Université de Strasbourg, Strasbourg, France.,

    Martin Karplus

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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). https://doi.org/10.1038/nchembio.565

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