Article

Rational design of proteins that exchange on functional timescales

  • Nature Chemical Biology 13, 12801285 (2017)
  • doi:10.1038/nchembio.2503
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Abstract

Proteins are intrinsically dynamic molecules that can exchange between multiple conformational states, enabling them to carry out complex molecular processes with extreme precision and efficiency. Attempts to design novel proteins with tailored functions have mostly failed to yield efficiencies matching those found in nature because standard methods do not allow the design of exchange between necessary conformational states on a functionally relevant timescale. Here we developed a broadly applicable computational method to engineer protein dynamics that we term meta-multistate design. We used this methodology to design spontaneous exchange between two novel conformations introduced into the global fold of Streptococcal protein G domain β1. The designed proteins, named DANCERs, for dynamic and native conformational exchangers, are stably folded and switch between predicted conformational states on the millisecond timescale. The successful introduction of defined dynamics on functional timescales opens the door to new applications requiring a protein to spontaneously access multiple conformational states.

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Biological Magnetic Resonance Data Bank

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Acknowledgements

R.A.C. acknowledges an Early Researcher Award from the Ontario Ministry of Economic Development & Innovation (ER14-10-139), and grants from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-04831) and the Canada Foundation for Innovation (26503). N.K.G. acknowledges a grant from NSERC (RGPIN-2011-20298378). J.A.D. is the recipient of an Ontario Graduate Scholarship and A.M.D. is the recipient of a NSERC postgraduate scholarship. We acknowledge G. Facey, Y. Aubin, and S. Sauvé for assistance with NMR experiments, as well as Y. Mou for helpful discussions.

Author information

Author notes

    • James A Davey
    •  & Adam M Damry

    These authors contributed equally to this work.

Affiliations

  1. Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada.

    • James A Davey
    • , Adam M Damry
    • , Natalie K Goto
    •  & Roberto A Chica

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Contributions

J.A.D. performed all computational experiments. A.M.D. and J.A.D. performed biophysical characterization experiments. A.M.D. performed all NMR experiments. N.K.G. and A.M.D. designed NMR experiments and analyzed data. J.A.D. and R.A.C. conceived the project, designed computational experiments and analyzed data. All authors wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Natalie K Goto or Roberto A Chica.

Supplementary information

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    Supplementary Results, Supplementary Tables 1–3, Supplementary Figures 1–12

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