Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Absolute comparison of simulated and experimental protein-folding dynamics

Nature volume 420, pages 102–106 (2002)Cite this article

Abstract

Protein folding is difficult to simulate with classical molecular dynamics. Secondary structure motifs such as α-helices and β-hairpins can form in 0.1–10 µs (ref. 1), whereas small proteins have been shown to fold completely in tens of microseconds2. The longest folding simulation to date is a single 1-µs simulation of the villin headpiece3; however, such single runs may miss many features of the folding process as it is a heterogeneous reaction involving an ensemble of transition states4,5. Here, we have used a distributed computing implementation to produce tens of thousands of 5–20-ns trajectories (700 µs) to simulate mutants of the designed mini-protein BBA5. The fast relaxation dynamics these predict were compared with the results of laser temperature-jump experiments. Our computational predictions are in excellent agreement with the experimentally determined mean folding times and equilibrium constants. The rapid folding of BBA5 is due to the swift formation of secondary structure. The convergence of experimentally and computationally accessible timescales will allow the comparison of absolute quantities characterizing in vitro and in silico (computed) protein folding6.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Folding results.
Figure 2: BBA5 double mutant thermodynamics and kinetics.
Figure 3: Folded population growth.

Similar content being viewed by others

References

  1. Eaton, W. A., Muñoz, V., Thompson, P. A., Henry, E. R. & Hofrichter, J. Kinetics and dynamics of loops, α-helices, β-hairpins, and fast-folding proteins. Acc. Chem. Res. 31, 745–753 (1998)

    Article  CAS  Google Scholar 

  2. Mayor, U., Johnson, C. M., Daggett, V. & Fersht, A. R. Protein folding and unfolding in microseconds to nanoseconds by experiment and simulation. Proc. Natl Acad. Sci. USA 97, 13518–13522 (2000)

    Article  ADS  CAS  Google Scholar 

  3. Duan, Y. & Kollman, P. A. Pathways to a protein folding intermediate observed in a 1-microsecond simulation in aqueous solution. Science 282, 740–744 (1998)

    Article  ADS  CAS  Google Scholar 

  4. Wolynes, P. G., Onuchic, J. N. & Thirumalai, D. Navigating the folding routes. Science 267, 1619–1620 (1995)

    Article  ADS  CAS  Google Scholar 

  5. Dill, K. A. & Chan, H. S. From Levinthal to pathways to funnels. Nature Struct. Biol. 4, 10–19 (1997)

    Article  CAS  Google Scholar 

  6. Shea, J. & Brooks, C. L. From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding. Annu. Rev. Phys. Chem. 52, 499–535 (2001)

    Article  ADS  CAS  Google Scholar 

  7. Ferrara, P., Apostolakis, J. & Caflisch, A. Thermodynamics and kinetics of folding of two model peptides investigated by molecular dynamics simulations. J. Phys. Chem. B 104, 5000–5010 (2000)

    Article  CAS  Google Scholar 

  8. Daura, X., Jaun, B., Seebach, D., Gunsteren, W. F. v. & Mark, A. E. Reversible peptide folding in solution by molecular dynamics simulation. J. Mol. Biol. 280, 925–932 (1998)

    Article  CAS  Google Scholar 

  9. Ferrara, P. & Caflisch, A. Folding simulations of a three-stranded antiparallel β-sheet peptide. Proc. Natl Acad. Sci. USA 97, 10780–10785 (2000)

    Article  ADS  CAS  Google Scholar 

  10. Zagrovic, B., Sorin, E. J. & Pande, V. S. β-hairpin folding simulations in atomistic detail using an implicit solvent model. J. Mol. Biol. 313, 151–169 (2001)

    Article  CAS  Google Scholar 

  11. Fersht, A. R., Matouschek, A. & Serrano, L. The folding of an enzyme I. Theory of protein engineering analysis of stability and pathway of protein folding. J. Mol. Biol. 224, 771–782 (1992)

    Article  CAS  Google Scholar 

  12. Lapidus, L. J., Eaton, W. A. & Hofrichter, J. Measuring the rate of intramolecular contact formation in polypeptides. Proc. Natl Acad. Sci. USA 97, 7220–7225 (2000)

    Article  ADS  CAS  Google Scholar 

  13. Bieri, O. et al. The speed limit of protein folding measure by triplet-triplet energy transfer. Proc. Natl Acad. Sci. USA 96, 9597–9601 (1999)

    Article  ADS  CAS  Google Scholar 

  14. Shirts, M. & Pande, V. S. Screen savers of the world unite. Science 290, 1903–1904 (2000)

    Article  CAS  Google Scholar 

  15. Struthers, M., Ottesen, J. J. & Imperiali, B. Design and NMR analyses of compact, independently folded BBA motifs. Folding Des. 3, 95–103 (1998)

    Article  CAS  Google Scholar 

  16. Struthers, M. D., Cheng, R. C. & Imperiali, B. Design of a monomeric 23-residue polypeptide with defined tertiary structure. Science 271, 342–345 (1996)

    Article  ADS  CAS  Google Scholar 

  17. Ervin, J., Sabelko, J. & Gruebele, M. Submicrosecond real-time fluorescence detection: application to protein folding. J. Photochem. Photobiol. Biol. 54, 1–15 (2000)

    Article  CAS  Google Scholar 

  18. Chandler, D. Statistical mechanics of isomerization dynamics in liquids and the transition state approximation. J. Chem. Phys. 68, 2959–2970 (1978)

    Article  ADS  CAS  Google Scholar 

  19. Gilmanshin, R., Williams, S., Callender, R. H., Woodruff, W. H. & Dyer, R. B. Fast events in protein folding: relaxation dynamics of secondary and tertiary structure in native apomyoglobin. Proc. Natl Acad. Sci. USA 94, 3709–3713 (1997)

    Article  ADS  CAS  Google Scholar 

  20. Ballew, R. M., Sabelko, J. & Gruebele, M. Direct observation of fast protein folding: the initial collapse of apomyoglobin. Proc. Natl Acad. Sci. USA 93, 5759–5764 (1996)

    Article  ADS  CAS  Google Scholar 

  21. Plaxco, K. W., Simons, K. T. & Baker, D. Contact order transition state placement and the refolding rates of single domain proteins. J. Mol. Biol. 277, 985–994 (1998)

    Article  CAS  Google Scholar 

  22. Moore, S. & Stein, W. Amino acid determination, methods and techniques. J. Biol. Chem. 192, 663–670 (1951)

    CAS  PubMed  Google Scholar 

  23. Ponder, J. W. & Richards, F. M. An efficient Newton-like method for molecular mechanics energy minimization of large molecules. J. Comput. Chem. 8, 1016–1024 (1987)

    Article  CAS  Google Scholar 

  24. Fletcher, R. & Powell, M. J. D. A rapidly convergent descent method for minimization. Comput. J. 6, 163–168 (1963)

    Article  MathSciNet  Google Scholar 

  25. Koehl, P. & Delarue, M. On the use of a self-consistent mean field theory to predict protein side chain conformations and estimate their entropies. J. Mol. Biol. 239, 249–275 (1994)

    Article  CAS  Google Scholar 

  26. Qiu, D., Shenkin, P. S., Hollinger, F. P. & Still, W. C. The GB/SA Continuum model for solvation. A fast analytical method for the calculation of approximate Born radii. J. Phys. Chem. A 101, 3005–3014 (1997)

    Article  CAS  Google Scholar 

  27. Jorgensen, W. L. & Tirado-Rives, J. The OPLS force field for proteins. Energy minimizations for crystals of cyclic peptides and crambin. J. Am. Chem. Soc. 110, 1657–1666 (1988)

    Article  CAS  Google Scholar 

  28. Andersen, H. C. Rattle: a ‘velocity’ version of the shake algorithm for molecular dynamics calculations. J. Comput. Phys. 52, 24–34 (1983)

    Article  ADS  CAS  Google Scholar 

  29. Kabsch, W. & Sander, C. Dictionary of protein secondary structure: pattern recognition of hydrogen-bonded and geometrical features. Biopolymers 22, 2577–2637 (1983)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Folding@Home volunteers whose processor power made this work possible; the members of the Pande, Levitt and Gruebele laboratories for discussion; J. Ottesen for the BBA5 coordinates; B. Imperiali for NMR data; the UIUC Laboratory for Fluorescence Dynamics; and the Suslick group for equipment use. C.S. was supported by a pre-doctoral Howard Hughes Medical Institute fellowship. V.P. and the Folding@Home project were supported by the National Institutes of Health (NIH), American Chemical Society-Petroleum Research Fund, National Science Foundation Materials Research Science & Engineering Centers, Center on Polymer Interfaces and Macromolecular Assemblies seed funds, and a gift from Intel. H.N. was supported by an NIH biophysics training grant. H.N. and M.G. were also funded by the NIH.

Author information

Author notes

  1. Christopher D. Snow, Houbi Nguyen and Martin Gruebele: These authors contributed equally to this work

Authors and Affiliations

  1. Biophysics Program and Department of Chemistry, Stanford University, Stanford, California, 94305-5080, USA

    Christopher D. Snow & Vijay S. Pande

  2. Departments of Chemistry and Physics, and Center for Biophysics and Computational Biology, University of Illinois, Urbana, Illinois, 61801, USA

    Houbi Nguyen & Martin Gruebele

Authors
  1. Christopher D. Snow
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Houbi Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vijay S. Pande
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martin Gruebele
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Vijay S. Pande or Martin Gruebele.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Snow, C., Nguyen, H., Pande, V. et al. Absolute comparison of simulated and experimental protein-folding dynamics. Nature 420, 102–106 (2002). https://doi.org/10.1038/nature01160

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01160

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing