Issue 20, 2021

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

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.

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

Supplementary files

Article information

Article type
Edge Article
Submitted
25 yan 2021
Accepted
13 apr 2021
First published
13 apr 2021
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2021,12, 6923-6928

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

W. M. Dawson, F. J. O. Martin, G. G. Rhys, K. L. Shelley, R. L. Brady and D. N. Woolfson, Chem. Sci., 2021, 12, 6923 DOI: 10.1039/D1SC00460C

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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