Skip to main content
NCBI home page
Biophysical Journal logoLink to Biophysical Journal
. 2001 Dec;81(6):3534–3544. doi: 10.1016/S0006-3495(01)75984-X

Analysis of multiple folding routes of proteins by a coarse-grained dynamics model.

B Erman 1
PMCID: PMC1301808  PMID: 11721014

Abstract

Langevin dynamics of a protein molecule with Go-type potentials is developed and used to analyze long time-scale events in the folding of cytochrome c. Several trajectories are generated, starting from random coil configurations and going to the native state, that are a few angstroms root mean square deviation (RMSD) from the native structure. The dynamics is controlled, to a large scale, by the two terminal helices that are in contact in the native state. These two helices form very early during folding, and depending on the trajectory, they either stabilize rapidly or break and re-form in going over steric barriers. The extended initial chain exhibits a rapid folding transition into a relatively compact shape, after which the helices are reorganized in a highly correlated manner. The time of formation of residue pair contacts strongly points to the hierarchical nature of folding; i.e., secondary structure forms first, followed by rearrangements of larger length scales at longer times. The kinetics of formation of native contacts is also analyzed, and the onset of a stable globular configuration, referred to as the molten globule in the literature, is identified. Predictions of the model are compared with extensive experimental data on cytochrome c.

Full Text

The Full Text of this article is available as a PDF (479.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akiyama S., Takahashi S., Ishimori K., Morishima I. Stepwise formation of alpha-helices during cytochrome c folding. Nat Struct Biol. 2000 Jun;7(6):514–520. doi: 10.1038/75932. [DOI] [PubMed] [Google Scholar]
  2. Alm E., Baker D. Matching theory and experiment in protein folding. Curr Opin Struct Biol. 1999 Apr;9(2):189–196. doi: 10.1016/S0959-440X(99)80027-X. [DOI] [PubMed] [Google Scholar]
  3. Baldwin R. L., Rose G. D. Is protein folding hierarchic? I. Local structure and peptide folding. Trends Biochem Sci. 1999 Jan;24(1):26–33. doi: 10.1016/s0968-0004(98)01346-2. [DOI] [PubMed] [Google Scholar]
  4. Baldwin R. L., Rose G. D. Is protein folding hierarchic? II. Folding intermediates and transition states. Trends Biochem Sci. 1999 Feb;24(2):77–83. doi: 10.1016/s0968-0004(98)01345-0. [DOI] [PubMed] [Google Scholar]
  5. Chan H. S., Dill K. A. Protein folding in the landscape perspective: chevron plots and non-Arrhenius kinetics. Proteins. 1998 Jan;30(1):2–33. doi: 10.1002/(sici)1097-0134(19980101)30:1<2::aid-prot2>3.0.co;2-r. [DOI] [PubMed] [Google Scholar]
  6. Clementi C., Vendruscolo M., Maritan A., Domany E. Folding Lennard-Jones proteins by a contact potential. Proteins. 1999 Dec 1;37(4):544–553. doi: 10.1002/(sici)1097-0134(19991201)37:4<544::aid-prot5>3.0.co;2-7. [DOI] [PubMed] [Google Scholar]
  7. Colón W., Elöve G. A., Wakem L. P., Sherman F., Roder H. Side chain packing of the N- and C-terminal helices plays a critical role in the kinetics of cytochrome c folding. Biochemistry. 1996 Apr 30;35(17):5538–5549. doi: 10.1021/bi960052u. [DOI] [PubMed] [Google Scholar]
  8. Colón W., Roder H. Kinetic intermediates in the formation of the cytochrome c molten globule. Nat Struct Biol. 1996 Dec;3(12):1019–1025. doi: 10.1038/nsb1296-1019. [DOI] [PubMed] [Google Scholar]
  9. Duan Y., Kollman P. A. Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science. 1998 Oct 23;282(5389):740–744. doi: 10.1126/science.282.5389.740. [DOI] [PubMed] [Google Scholar]
  10. Elöve G. A., Bhuyan A. K., Roder H. Kinetic mechanism of cytochrome c folding: involvement of the heme and its ligands. Biochemistry. 1994 Jun 7;33(22):6925–6935. doi: 10.1021/bi00188a023. [DOI] [PubMed] [Google Scholar]
  11. Elöve G. A., Chaffotte A. F., Roder H., Goldberg M. E. Early steps in cytochrome c folding probed by time-resolved circular dichroism and fluorescence spectroscopy. Biochemistry. 1992 Aug 4;31(30):6876–6883. doi: 10.1021/bi00145a003. [DOI] [PubMed] [Google Scholar]
  12. Englander S. W. Protein folding intermediates and pathways studied by hydrogen exchange. Annu Rev Biophys Biomol Struct. 2000;29:213–238. doi: 10.1146/annurev.biophys.29.1.213. [DOI] [PubMed] [Google Scholar]
  13. Galzitskaya O. V., Finkelstein A. V. A theoretical search for folding/unfolding nuclei in three-dimensional protein structures. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11299–11304. doi: 10.1073/pnas.96.20.11299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Go N. Theoretical studies of protein folding. Annu Rev Biophys Bioeng. 1983;12:183–210. doi: 10.1146/annurev.bb.12.060183.001151. [DOI] [PubMed] [Google Scholar]
  15. Hagen S. J., Eaton W. A. Two-state expansion and collapse of a polypeptide. J Mol Biol. 2000 Aug 25;301(4):1019–1027. doi: 10.1006/jmbi.2000.3969. [DOI] [PubMed] [Google Scholar]
  16. Hostetter D. R., Weatherly G. T., Beasley J. R., Bortone K., Cohen D. S., Finger S. A., Hardwidge P., Kakouras D. S., Saunders A. J., Trojak S. K. Partially formed native tertiary interactions in the A-state of cytochrome c. J Mol Biol. 1999 Jun 11;289(3):639–644. doi: 10.1006/jmbi.1999.2764. [DOI] [PubMed] [Google Scholar]
  17. Kuroda Y. Residual helical structure in the C-terminal fragment of cytochrome c. Biochemistry. 1993 Feb 9;32(5):1219–1224. doi: 10.1021/bi00056a004. [DOI] [PubMed] [Google Scholar]
  18. Laurents D. V., Baldwin R. L. Protein folding: matching theory and experiment. Biophys J. 1998 Jul;75(1):428–434. doi: 10.1016/S0006-3495(98)77530-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mayne L., Englander S. W. Two-state vs. multistate protein unfolding studied by optical melting and hydrogen exchange. Protein Sci. 2000 Oct;9(10):1873–1877. doi: 10.1110/ps.9.10.1873. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Muñoz V., Eaton W. A. A simple model for calculating the kinetics of protein folding from three-dimensional structures. Proc Natl Acad Sci U S A. 1999 Sep 28;96(20):11311–11316. doi: 10.1073/pnas.96.20.11311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Parker M. J., Marqusee S. A statistical appraisal of native state hydrogen exchange data: evidence for a burst phase continuum? J Mol Biol. 2000 Jul 28;300(5):1361–1375. doi: 10.1006/jmbi.2000.3922. [DOI] [PubMed] [Google Scholar]
  22. Plaxco K. W., Simons K. T., Baker D. Contact order, transition state placement and the refolding rates of single domain proteins. J Mol Biol. 1998 Apr 10;277(4):985–994. doi: 10.1006/jmbi.1998.1645. [DOI] [PubMed] [Google Scholar]
  23. Roder H., Elöve G. A., Englander S. W. Structural characterization of folding intermediates in cytochrome c by H-exchange labelling and proton NMR. Nature. 1988 Oct 20;335(6192):700–704. doi: 10.1038/335700a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sauder J. M., Roder H. Amide protection in an early folding intermediate of cytochrome c. Fold Des. 1998;3(4):293–301. doi: 10.1016/S1359-0278(98)00040-6. [DOI] [PubMed] [Google Scholar]
  25. Shastry M. C., Luck S. D., Roder H. A continuous-flow capillary mixing method to monitor reactions on the microsecond time scale. Biophys J. 1998 May;74(5):2714–2721. doi: 10.1016/S0006-3495(98)77977-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Shastry M. C., Roder H. Evidence for barrier-limited protein folding kinetics on the microsecond time scale. Nat Struct Biol. 1998 May;5(5):385–392. doi: 10.1038/nsb0598-385. [DOI] [PubMed] [Google Scholar]
  27. Sosnick T. R., Mayne L., Hiller R., Englander S. W. The barriers in protein folding. Nat Struct Biol. 1994 Mar;1(3):149–156. doi: 10.1038/nsb0394-149. [DOI] [PubMed] [Google Scholar]
  28. Takada S. Go-ing for the prediction of protein folding mechanisms. Proc Natl Acad Sci U S A. 1999 Oct 12;96(21):11698–11700. doi: 10.1073/pnas.96.21.11698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Wolynes P. G., Onuchic J. N., Thirumalai D. Navigating the folding routes. Science. 1995 Mar 17;267(5204):1619–1620. doi: 10.1126/science.7886447. [DOI] [PubMed] [Google Scholar]
  30. Wu L. C., Laub P. B., Elöve G. A., Carey J., Roder H. A noncovalent peptide complex as a model for an early folding intermediate of cytochrome c. Biochemistry. 1993 Sep 28;32(38):10271–10276. doi: 10.1021/bi00089a050. [DOI] [PubMed] [Google Scholar]
  31. Xu Y., Mayne L., Englander S. W. Evidence for an unfolding and refolding pathway in cytochrome c. Nat Struct Biol. 1998 Sep;5(9):774–778. doi: 10.1038/1810. [DOI] [PubMed] [Google Scholar]
  32. Yeh S. R., Rousseau D. L. Hierarchical folding of cytochrome c. Nat Struct Biol. 2000 Jun;7(6):443–445. doi: 10.1038/75831. [DOI] [PubMed] [Google Scholar]
  33. Yeh S. R., Takahashi S., Fan B., Rousseau D. L. Ligand exchange during cytochrome c folding. Nat Struct Biol. 1997 Jan;4(1):51–56. doi: 10.1038/nsb0197-51. [DOI] [PubMed] [Google Scholar]

Articles from Biophysical Journal are provided here courtesy of The Biophysical Society

RESOURCES