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Structure of (KIAGKIA)₃ Aggregates in Phospholipid Bilayers by Solid-State NMR

Orsolya Toke ^*, R. D. O'Connor ^*, Thomas K. Weldeghiorghis ^*, W. Lee Maloy ^*, Ralf W. Glaser  , Anne S. Ulrich  and Jacob Schaefer ^*

^* Department of Chemistry, Washington University, St. Louis, Missouri 63130 USA; Genaera Pharmaceuticals, Plymouth Meeting, Pennsylvania 19462 USA; Institute of Organic Chemistry, University of Karlsruhe, Fritz-Haber-Weg 6, 76131 Karlsruhe, Germany; and Institute of Biochemistry and Biophysics, Friedrich-Schiller-University, 07745 Jena, Germany

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

The interchain ¹³C-¹⁹F dipolar coupling measured in a rotational-echo double-resonance (REDOR) experiment performed on mixtures of differently labeled KIAGKIA-KIAGKIA-KIAGKIA (K3) peptides (one specifically ¹³C labeled, and the other specifically ¹⁹F labeled) in multilamellar vesicles of dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol (1:1) shows that K3 forms close-packed clusters, primarily dimers, in bilayers at a lipid/peptide molar ratio (L/P) of 20. Dipolar coupling to additional peptides is weaker than that within the dimers, consistent with aggregates of monomers and dimers. Analysis of the sideband dephasing rates indicates a preferred orientation between the peptide chains of the dimers. The combination of the distance and orientation information from REDOR is consistent with a parallel (N–N) dimer structure in which two K3 helices intersect at a cross-angle of 20°. Static ¹⁹F NMR experiments performed on K3 in oriented lipid bilayers show that between L/P = 200 and L/P = 20, K3 chains change their absolute orientation with respect to the membrane normal. This result suggests that the K3 dimers detected by REDOR at L/P = 20 are not on the surface of the bilayer but are in a membrane pore.

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