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Rational design of proteins that exchange on functional timescales

James A. Davey, Adam M. Damry, Natalie K. Goto, Roberto A. Chica
doi: https://doi.org/10.1101/113845
James A. Davey
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
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Adam M. Damry
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
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Natalie K. Goto
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
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  • For correspondence: rchica@uottawa.ca ngoto@uottawa.ca
Roberto A. Chica
Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
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  • For correspondence: rchica@uottawa.ca ngoto@uottawa.ca
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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 for the design of exchange between necessary conformational states on a functionally-relevant timescale. Here, we develop 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 exchange 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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Posted March 03, 2017.
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Rational design of proteins that exchange on functional timescales
James A. Davey, Adam M. Damry, Natalie K. Goto, Roberto A. Chica
bioRxiv 113845; doi: https://doi.org/10.1101/113845
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Rational design of proteins that exchange on functional timescales
James A. Davey, Adam M. Damry, Natalie K. Goto, Roberto A. Chica
bioRxiv 113845; doi: https://doi.org/10.1101/113845

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