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

DOI: 10.1039/D1SC00460C DOI Help

Authors: William Michael Dawson (University of Bristol) , Freddie Jo Martin (University of Bristol) , Guto G. Rhys (University of Bristol; University of Bayreuth) , Kathryn L. Shelley (University of Bristol) , R. Leo Brady (University of Bristol) , Derek Woolfson (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Chemical Science

State: Published (Approved)
Published: April 2021
Diamond Proposal Number(s): 12342 , 23269

Open Access Open Access

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.

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Added On: 21/04/2021 08:38


Discipline Tags:

Biochemistry Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)