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Structural resolution of switchable states of a de novo peptide assembly

DOI: 10.1038/s41467-021-21851-8 DOI Help

Authors: William M. Dawson (University of Bristol) , Eric J. M. Lang (University of Bristol) , Guto G. Rhys (University of Bristol; University of Bayreuth) , Kathryn L. Shelley (University of Bristol) , Christopher Williams (University of Bristol) , R. Leo Brady (University of Bristol) , Matthew P. Crump (University of Bristol) , Adrian J. Mulholland (University of Bristol) , Derek N. Woolfson (University of Bristol)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 12

State: Published (Approved)
Published: March 2021

Open Access Open Access

Abstract: De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally.

Subject Areas: Biology and Bio-materials

Instruments: I24-Microfocus Macromolecular Crystallography

Added On: 16/03/2021 14:16


Discipline Tags:

Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)