Energy landscape and multiroute folding of topologically complex proteins adenylate kinase and 2ouf-knot

Edited by William A. Eaton, National Institutes of Health-NIDDK, Bethesda, MD, and approved June 4, 2012 (received for review March 14, 2012)
July 2, 2012
109 (44) 17789-17794

Abstract

While fast folding of small proteins has been relatively well characterized by experiments and theories, much less is known for slow folding of larger proteins, for which recent experiments suggested quite complex and rich folding behaviors. Here, we address how the energy landscape theory can be applied to these slow folding reactions. Combining the perfect-funnel approximation with a multiscale method, we first extended our previous atomic-interaction based coarse grained (AICG) model to take into account local flexibility of protein molecules. Using this model, we then investigated the energy landscapes and folding routes of two proteins with complex topologies: a multidomain protein adenylate kinase (AKE) and a knotted protein 2ouf-knot. In the AKE folding, consistent with experimental results, the kinetic free energy surface showed several substates between the fully unfolded and native states. We characterized the structural features of these substates and transitions among them, finding temperature-dependent multiroute folding. For protein 2ouf-knot, we found that the improved atomic-interaction based coarse-grained model can spontaneously tie a knot and fold the protein with a probability up to 96%. The computed folding rate of the knotted protein was much slower than that of its unknotted counterpart, in agreement with experimental findings. Similar to the AKE case, the 2ouf-knot folding exhibited several substates and transitions among them. Interestingly, we found a dead-end substate that lacks the knot, thus suggesting backtracking mechanisms.

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ACKNOWLEDGMENTS.

This work was based on a joint project between the Japan Society for the Promotion of Science and the National Natural Science Foundation of China, partly supported by Grant-in-Aid for Scientific Research on Innovative Areas “Molecular Science of Fluctuations Toward Biological Functions,” by Research and Development of the Next-Generation Integrated Simulation of Living Matter of the Ministry of Education, Culture, Sports, Science, and Technology, by the National Natural Science Foundation of China (Grants Nos. 11111140012, 11174134, 91127026, and 10834002), and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Information & Authors

Information

Published in

Go to Proceedings of the National Academy of Sciences
Proceedings of the National Academy of Sciences
Vol. 109 | No. 44
October 30, 2012
PubMed: 22753508

Classifications

Submission history

Published online: July 2, 2012
Published in issue: October 30, 2012

Keywords

  1. protein folding
  2. molecular dynamics simulations
  3. multiscale simulations
  4. flexible local potential
  5. topological frustrations

Acknowledgments

This work was based on a joint project between the Japan Society for the Promotion of Science and the National Natural Science Foundation of China, partly supported by Grant-in-Aid for Scientific Research on Innovative Areas “Molecular Science of Fluctuations Toward Biological Functions,” by Research and Development of the Next-Generation Integrated Simulation of Living Matter of the Ministry of Education, Culture, Sports, Science, and Technology, by the National Natural Science Foundation of China (Grants Nos. 11111140012, 11174134, 91127026, and 10834002), and by a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Notes

This article is a PNAS Direct Submission.

Authors

Affiliations

Wenfei Li
National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210093, China;
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan; and
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan
Tsuyoshi Terakawa
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan; and
National Laboratory of Solid State Microstructure and Department of Physics, Nanjing University, Nanjing 210093, China;
Shoji Takada1 [email protected]
Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan; and
Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan

Notes

1
To whom correspondence may be addressed. E-mail: [email protected] or [email protected].
Author contributions: W.L. and S.T. designed research; W.L. and S.T. performed research; W.L., T.T., and S.T. contributed new reagents/analytic tools; W.L., T.T., W.W., and S.T. analyzed data; and W.L., T.T., W.W., and S.T. wrote the paper.

Competing Interests

The authors declare no conflict of interest.

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    Energy landscape and multiroute folding of topologically complex proteins adenylate kinase and 2ouf-knot
    Proceedings of the National Academy of Sciences
    • Vol. 109
    • No. 44
    • pp. 17725-18233

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