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Coiled coils 9-to-5: rational de novo design of α-helical barrels with tunable oligomeric states

Dawson, William M., Martin, Freddie J. O., Rhys, Guto G., Shelley, Kathryn L., Brady, R. Leo and Woolfson, Derek N. 2021. Coiled coils 9-to-5: rational de novo design of α-helical barrels with tunable oligomeric states. Chemical Science 12 (20) , pp. 6923-6928. 10.1039/D1SC00460C

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Abstract

The rational design of linear peptides that assemble controllably and predictably in water is challenging. Short sequences must encode unique target structures and avoid alternative states. However, the non-covalent forces that stabilize and discriminate between states are weak. Nonetheless, for α-helical coiled-coil assemblies considerable progress has been made in rational de novo design. In these, sequence repeats of nominally hydrophobic (h) and polar (p) residues, hpphppp, direct the assembly of amphipathic helices into dimeric to tetrameric bundles. Expanding this pattern to hpphhph can produce larger α-helical barrels. Here, we show that pentameric to nonameric barrels are accessed by varying the residue at one of the h sites. In peptides with four L/I–K–E–I–A–x–Z repeats, decreasing the size of Z from threonine to serine to alanine to glycine gives progressively larger oligomers. X-ray crystal structures of the resulting α-helical barrels rationalize this: side chains at Z point directly into the helical interfaces, and smaller residues allow closer helix contacts and larger assemblies.

Item Type: Article
Status: Published
Schools: Chemistry
Additional Information: This article is licensed under a Creative Commons Attribution 3.0 Unported Licence
Publisher: Royal Society of Chemistry
ISSN: 2041-6520
Funders: EPSRC and BBSRC
Date of First Compliant Deposit: 25 October 2022
Date of Acceptance: 13 April 2021
Last Modified: 07 May 2023 02:30
URI: https://orca.cardiff.ac.uk/id/eprint/153754

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