Measuring Screw-Sense Preference in Peptide Foldamers with a Chiral 19F NMR Reporter

Abstract

G-protein coupled receptors (GPCRs) are membrane-embedded proteins that transmit signals through bilayer membranes. Chemists, inspired by nature, have developed synthetic foldamers (folded oligomers) that can adopt defined structures like biomolecules such as proteins. Previous studies showed that conformationally dynamic synthetic foldamers composed of Aib (2-aminoisobutyric acid) are able to relay structural information across distances on a nanometer scale similar to GPCRs. Understanding and controlling Aib foldamer conformation in phospholipid bilayers is therefore essential, which will allow the foldamers to be used as molecular information relays in membrane environments. In this thesis, a series of Aib tetramers and octamers with a chiral amino acid residue on the N-terminus and a new chiral 19F NMR reporter, (R)-TFEA ((R)-1-trifluoromethyl-ethylamido), on the C-terminus are studied. The chiral residues were covalent controllers that induced a helical preference in the foldamers, allowing the performance of the (R)-TFEA reporter to be validated in different environments. Spectroscopic studies were first performed in organic solution using IR (infrared), CD (circular dichroism) and 19F NMR (nuclear magnetic resonance) spectroscopy. The types of helices adopted by the foldamers and the helical preference induced by each controller are discussed based on the spectroscopic data. X-ray diffraction (XRD) analysis of the foldamers is also discussed; the XRD data confirmed that the foldamers adopted 310 helices. Spectroscopic studies were then performed on small unilamellar vesicle (SUV) suspensions, aiming to explore the behaviours of the Aib tetramers and octamers in bilayer membranes. Lanthanide shift reagents (LSRs) were also employed to study the orientation of octameric Aib foldamers in SUVs since octamers have a comparable length with the membrane thickness.

Date of Award	31 Dec 2023
Original language	English
Awarding Institution	The University of Manchester
Supervisor	John Gardiner (Supervisor) & Simon Webb (Supervisor)