A Chiral F NMR Reporter of Foldamer Conformation in Bilayers.

Understanding and controlling peptide foldamer conformation in phospholipid bilayers is a key step toward their use as molecular information relays in membranes. To this end, a new F "reporter" tag has been developed and attached to dynamic peptide foldamers. The ()-1-(trifluoromethyl)ethylamido (()-TFEA) reporter was attached to the C-terminus of α-amino--butyric acid (Aib) foldamers. Crystallography confirmed that the foldamers adopted 3 helical conformations. Variable temperature (VT) NMR spectroscopy in organic solvents showed that the ()-TFEA reporter had an intrinsic preference for helicity, but the overall screw-sense was dominated by a chiral "controller" at the N-terminus. The F NMR chemical shift of the CF resonance was correlated with the ability of different N-terminal groups to induce either an or a helix in solution. In bilayers, a similar correlation was found. Solution F NMR spectroscopy on small unilamellar vesicle (SUV) suspensions containing the same family of ()-TFEA-labeled foldamers showed broadened but resolvable F resonances, with each chemical shift mirroring their relative positions in organic solvents. These studies showed that foldamer conformational preferences are the same in phospholipid bilayers as in organic solvents and also revealed that phospholipid chirality has little influence on conformation.