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De novo design of proteins with two isoenergetic but structurally divergent ground states

View ORCID ProfileKathy Y. Wei, Danai Moschidi, View ORCID ProfileMatthew J. Bick, Santrupti Nerli, View ORCID ProfileAndrew C. McShan, Lauren P. Carter, View ORCID ProfilePo-Ssu Huang, View ORCID ProfileDaniel A. Fletcher, View ORCID ProfileNikolaos G. Sgourakis, Scott E. Boyken, View ORCID ProfileDavid Baker
doi: https://doi.org/10.1101/597161
Kathy Y. Wei
Department of Biochemistry, University of Washington, Seattle, WA 98195, USAInstitute for Protein Design, University of Washington, Seattle, WA 98195, USADepartment of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA
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Danai Moschidi
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Matthew J. Bick
Department of Biochemistry, University of Washington, Seattle, WA 98195, USAInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Santrupti Nerli
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USADepartment of Computer Science, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Andrew C. McShan
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Lauren P. Carter
Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Po-Ssu Huang
Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Daniel A. Fletcher
Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USAUC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USADivision of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USAChan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Nikolaos G. Sgourakis
Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Scott E. Boyken
Department of Biochemistry, University of Washington, Seattle, WA 98195, USAInstitute for Protein Design, University of Washington, Seattle, WA 98195, USA
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  • For correspondence: dabaker@u.washington.edu
David Baker
Department of Biochemistry, University of Washington, Seattle, WA 98195, USAInstitute for Protein Design, University of Washington, Seattle, WA 98195, USAHoward Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
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  • For correspondence: dabaker@u.washington.edu
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Abstract

The plasticity of naturally occurring protein structures, which can change shape considerably in response to changes in environmental conditions, is critical to biological function. For example, class I viral fusion proteins undergo large scale conformational changes from a pre-fusion to a post-fusion structure critical for the virus to enter cells(Ivanovic et al., 2013; Podbilewicz, 2014; Skehel and Wiley, 2000). While computational methods have been used to de novo design proteins in single deep free energy minima(Huang et al., 2016), designing sequences with two well-separated free energy minima corresponding to well-defined, but divergent structures is substantially more challenging, and has not yet been achieved. Here, we design sequences which can adopt two very different homotrimeric helical bundle conformations -- one short (~66 Å height) and the other long (~100 Å height) -- reminiscent of the conformational transition of viral fusion proteins. Crystallographic and NMR spectroscopic characterization of a set of closely related sequences show that both the short and long structures fold as designed, and suggest that the two states are nearly isoenergetic as small sequence changes and/or changes in measurement conditions switch the observed state.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted April 04, 2019.
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De novo design of proteins with two isoenergetic but structurally divergent ground states
Kathy Y. Wei, Danai Moschidi, Matthew J. Bick, Santrupti Nerli, Andrew C. McShan, Lauren P. Carter, Po-Ssu Huang, Daniel A. Fletcher, Nikolaos G. Sgourakis, Scott E. Boyken, David Baker
bioRxiv 597161; doi: https://doi.org/10.1101/597161
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De novo design of proteins with two isoenergetic but structurally divergent ground states
Kathy Y. Wei, Danai Moschidi, Matthew J. Bick, Santrupti Nerli, Andrew C. McShan, Lauren P. Carter, Po-Ssu Huang, Daniel A. Fletcher, Nikolaos G. Sgourakis, Scott E. Boyken, David Baker
bioRxiv 597161; doi: https://doi.org/10.1101/597161

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