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Navigating the structural landscape of de novo α-helical bundles

View ORCID ProfileGuto G. Rhys, View ORCID ProfileChristopher W. Wood, View ORCID ProfileJoseph L. Beesley, View ORCID ProfileNathan R. Zaccai, View ORCID ProfileAntony J. Burton, View ORCID ProfileR. Leo Brady, View ORCID ProfileAndrew R. Thomson, View ORCID ProfileDerek N. Woolfson
doi: https://doi.org/10.1101/503698
Guto G. Rhys
University of Bristol;
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Christopher W. Wood
University of Edinburgh;
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Joseph L. Beesley
University of Bristol;
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Nathan R. Zaccai
University of Cambridge;
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Antony J. Burton
Princeton University;
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R. Leo Brady
University of Bristol;
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Andrew R. Thomson
University of Glasgow
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Derek N. Woolfson
University of Bristol;
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  • For correspondence: d.n.woolfson@bristol.ac.uk
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Abstract

The association of amphipathic α helices in water leads to α-helical-bundle protein structures. However, the driving force for this--the hydrophobic effect--is not specific and does not define the number or the orientation of helices in the associated state. Rather, this is achieved through deeper sequence-to-structure relationships, which are increasingly being discerned. For example, for one structurally extreme but nevertheless ubiquitous class of bundle--the α-helical coiled coils--relationships have been established that discriminate between all-parallel dimers, trimers and tetramers. Association states above this are known, as are antiparallel and mixed arrangements of the helices. However, these alternative states are less-well understood. Here, we describe a synthetic-peptide system that switches between parallel hexamers and various up-down-up-down tetramers in response to single-amino-acid changes and solution conditions. The main accessible states of each peptide variant are characterized fully in solution and, in most cases, to high-resolution X-ray crystal structures. Analysis and inspection of these structures helps rationalize the different states formed. This navigation of the structural landscape of α-helical coiled coils above the dimers and trimers that dominate in nature has allowed us to design rationally a well-defined and hyperstable antiparallel coiled-coil tetramer (apCC-Tet). This robust de novo protein provides another scaffold for further structural and functional designs in protein engineering and synthetic biology.

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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 December 21, 2018.
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Navigating the structural landscape of de novo α-helical bundles
Guto G. Rhys, Christopher W. Wood, Joseph L. Beesley, Nathan R. Zaccai, Antony J. Burton, R. Leo Brady, Andrew R. Thomson, Derek N. Woolfson
bioRxiv 503698; doi: https://doi.org/10.1101/503698
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Navigating the structural landscape of de novo α-helical bundles
Guto G. Rhys, Christopher W. Wood, Joseph L. Beesley, Nathan R. Zaccai, Antony J. Burton, R. Leo Brady, Andrew R. Thomson, Derek N. Woolfson
bioRxiv 503698; doi: https://doi.org/10.1101/503698

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