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Secondary Structure and Lipid Contact of a Peptide Antibiotic in Phospholipid Bilayers by REDOR

Orsolya Toke ^*, W. Lee Maloy , Sung Joon Kim , Jack Blazyk  and Jacob Schaefer ^*

^* Department of Chemistry, Washington University, St. Louis, Missouri 63130; Genaera Pharmaceuticals, Plymouth Meeting, Pennsylvania 19462; Department of Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri 63130; Department of Biomedical Sciences, College of Osteopathic Medicine and Department of Chemistry and Biochemistry, College of Arts and Sciences, Ohio University, Athens, Ohio 45701

Correspondence: Address reprint requests to Jacob Schaefer, Dept. of Chemistry, Washington University, 1 Brookings Dr., St. Louis, MO 63130. Tel.: 314-935-6844; Fax: 314-935-4481; E-mail: schaefer{at}wuchem.wustl.edu

The chemical shifts of specific ¹³C and ¹⁵N labels distributed throughout KIAGKIA-KIAGKIA-KIAGKIA (K3), an amphiphilic 21-residue antimicrobial peptide, prove that the peptide is in an all -helical conformation in the bilayers of multilamellar vesicles (MLVs) containing dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (1:1). Rotational-echo double-resonance (REDOR) ¹³C{³¹P} and ¹⁵N{³¹P} experiments on the same labeled MLVs show that on partitioning into the bilayer, the peptide chains remain in contact with lipid headgroups. The amphipathic lysine side chains of K3 in particular appear to play a key role in the electrostatic interactions with the acidic lipid headgroups. In addition to the extensive peptide-headgroup contact, ¹³C{¹⁹F} REDOR experiments on MLVs containing specifically ¹⁹F-labeled lipid tails suggest that a portion of the peptide is surrounded by a large number of lipid acyl chains. Complementary ³¹P{¹⁹F} REDOR experiments on these MLVs show an enhanced headgroup-lipid tail contact resulting from the presence of K3. Despite these distortions, static ³¹P NMR lineshapes indicate that the lamellar structure of the membrane is preserved.

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