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Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds

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
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
3Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA
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  • For correspondence: kat.wei@gmail.com
Danai Moschidi
4Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Matthew J. Bick
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Santrupti Nerli
4Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
5Department of Computer Science, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Andrew C. McShan
4Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Lauren P. Carter
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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Po-Ssu Huang
6Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Daniel A. Fletcher
3Department of Bioengineering, University of California, Berkeley, Berkeley, CA 94720, USA
7UC Berkeley/UC San Francisco Graduate Group in Bioengineering, Berkeley, CA 94720, USA
8Division of Biological Systems and Engineering, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA
9Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Nikolaos G. Sgourakis
4Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA 95064, USA
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Scott E. Boyken
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
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David Baker
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA
2Institute for Protein Design, University of Washington, Seattle, WA 98195, USA
10Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA
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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. While computational methods have been used to de novo design proteins that fold to a single state with a deep free energy minima (Huang et al., 2016), and to reengineer natural proteins to alter their dynamics (Davey et al., 2017) or fold (Alexander et al., 2009), the de novo design of closely related sequences which adopt well-defined, but structurally divergent structures remains an outstanding challenge. Here, we design closely related sequences (over 94% identity) that 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 (Ivanovic et al., 2013; Podbilewicz, 2014; Skehel and Wiley, 2000). Crystallographic and NMR spectroscopic characterization show that both the short and long state sequences fold as designed. We sought to design bistable sequences for which both states are accessible, and obtained a single designed protein sequence that populates either the short state or the long state depending on the measurement conditions. The design of sequences which are poised to adopt two very different conformations sets the stage for creating large scale conformational switches between structurally divergent forms.

Footnotes

  • Updated text and Figure 4.

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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. All rights reserved. No reuse allowed without permission.
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Posted September 04, 2019.
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Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds
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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Computational design of a protein family that adopts two well-defined and structurally divergent de novo folds
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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