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Cryo-EM, XFELs and the structure conundrum in structural biology

Single-particle techniques offer an unprecedented opportunity to understand the role of structural variability in biological function. They also call into question the meaning of ‘a structure’ and its relevance to function.

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Fig. 1: Hypersurface representing all possible conformations of a molecule.
Fig. 2: Experimentally determined conformational motions and energy landscape of a ribosome.
Fig. 3: Four frames of a 50-frame movie showing the conformational changes in the PR772 virus.

References

  1. Ramachandran, G. N., Ramakrishnan, C. & Sasisekharan, V. J. Mol. Biol. 7, 95–99 (1963).

    Article  CAS  Google Scholar 

  2. Frauenfelder, H., Sligar, S. G. & Wolynes, P. G. Science 254, 1598–1603 (1991).

    Article  CAS  Google Scholar 

  3. Dashti, A. et al. Proc. Natl. Acad. Sci. USA 111, 17492–17497 (2014).

    Article  CAS  Google Scholar 

  4. Henzler-Wildman, K. & Kern, D. Nature 450, 964–972 (2007).

    Article  CAS  Google Scholar 

  5. Frank, J. Biochemistry 57, 888 (2018).

    Article  CAS  Google Scholar 

  6. Ourmazd, A. in X-Ray Free Electron Lasers: Applications in Materials, Chemistry and Biology Energy and Environment Series (eds Uwe Bergmann, V. Yachandra & J. Yano) 418–433 (Royal Society of Chemistry, 2017).

  7. Fischer, N., Konevega, A. L., Wintermeyer, W., Rodnina, M. V. & Stark, H. Nature 466, 329–333 (2010).

    Article  CAS  Google Scholar 

  8. Neu, J. C., Ghanta, A. & Teitsworth, S. in Coupled Mathematical Models for Physical and Biological Nanoscale Systems and Their Applications Vol. 232 Springer Proceedings in Mathematics and Statistics (eds Bonilla, L. L. et al.) 153–167 (Springer 2018).

  9. Frank, J. & Ourmazd, A. Methods 100, 61–67 (2016).

    Article  CAS  Google Scholar 

  10. Dashti, A. et al. Preprint at https://doi.org/10.1101/291922 (2019).

  11. Pande, K. et al. Science 352, 725–729 (2016).

    Article  CAS  Google Scholar 

  12. Kupitz, C. et al. Nature 513, 261–265 (2014).

    Article  CAS  Google Scholar 

  13. Boutet, S. et al. Science 337, 362–364 (2012).

    Article  CAS  Google Scholar 

  14. Hosseinizadeh, A., Dashti, A., Schwander, P., Fung, R. & Ourmazd, A. Struc. Dyn. 2, 041601 (2015).

    Article  CAS  Google Scholar 

  15. Gaffney, K. J. & Chapman, H. N. Science 316, 1444–1448 (2007).

    Article  CAS  Google Scholar 

  16. Neutze, R., Wouts, R., van der Spoel, D., Weckert, E. & Hajdu, J. Nature 406, 752–757 (2000).

    Article  CAS  Google Scholar 

  17. Ekeberg, T. et al. Phys. Rev. Lett. 114, 098102 (2015).

    Article  Google Scholar 

  18. Hosseinizadeh, A. et al. Nat. Meth. 14, 877–881 (2017).

    Article  CAS  Google Scholar 

  19. Munke, A. et al. Sci. Data 3, 160064 (2016).

    Article  Google Scholar 

  20. Ayyer, K. et al. Preprint at https://arxiv.org/abs/1905.05008 (2019).

  21. von Ardenne, B., Mechelke, M. & Grubmuller, H. Nat. Commun. 9, 2375 (2018).

    Article  Google Scholar 

  22. Neugebauer, J., Reiher, M., Kind, C. & Hess, B. A. J. Comput. Chem. 23, 895–910 (2002).

    Article  CAS  Google Scholar 

  23. Jarzynski, C. Phys. Rev. Lett. 78, 2690–2693 (1997).

    Article  CAS  Google Scholar 

  24. Jarzynski, C. Phys. Rev. 56, 5018–5035 (1997).

    CAS  Google Scholar 

  25. Crooks, G. E. Phys. Rev. 61, 2361 (2000).

    CAS  Google Scholar 

  26. Pohorille, A., Jarzynski, C. & Chipot, C. J. Phys. Chem. 114, 10235–10253 (2010).

    Article  CAS  Google Scholar 

  27. Fung, R., Shneerson, V., Saldin, D. K. & Ourmazd, A. Nat. Phys. 5, 64–67 (2009).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

I am indebted to my colleagues at the University of Wisconsin Milwaukee for many discussions, and to J. Frank, A. Singharoy for valuable comments on the manuscript. The research conducted at the University of Wisconsin Milwaukee was supported by the US Department of Energy, Office of Science, Basic Energy Sciences under award DE-SC0002164 (algorithm design and development), and by the US National Science Foundation under awards STC 1231306 (numerical trial models and data analysis) and 1551489 (underlying analytical models).

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Ourmazd, A. Cryo-EM, XFELs and the structure conundrum in structural biology. Nat Methods 16, 941–944 (2019). https://doi.org/10.1038/s41592-019-0587-4

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