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Structural Restraints and Heterogeneous Orientation of the Gramicidin A Channel Closed State in Lipid Bilayers

Y. Mo ^* , T.A. Cross ^*   and W. Nerdal ^*  

^* National High Magnetic Field Laboratory, and Department of Chemistry and Biochemistry and Institute of Molecular Biophysics, Florida State University, Tallahassee, Florida; and Department of Chemistry, University of Bergen, Bergen, Norway

Correspondence: Address reprint requests to T. A. Cross, National High Magnetic Field Laboratory, 1800 E. Dirac Dr., Tallahassee, FL 32310. E-mail: cross{at}magnet.fsu.edu.

Although there have been several decades of literature illustrating the opening and closing of the monovalent cation selective gramicidin A channel through single channel conductance, the closed conformation has remained poorly characterized. In sharp contrast, the open-state dimer is one of the highest resolution structures yet characterized in a lipid environment. To shift the open/closed equilibrium dramatically toward the closed state, a lower peptide/lipid molar ratio and, most importantly, long-chain lipids have been used. For the first time, structural evidence for a monomeric state has been observed for the native gramicidin A peptide. Solid-state NMR spectroscopy of single-site ¹⁵N-labeled gramicidin in uniformly aligned bilayers in the L phase have been observed. The results suggest a kinked structure with considerable orientational heterogeneity. The C-terminal domain is well structured, has a well-defined orientation in the bilayer, and appears to be in the bilayer interfacial region. On the other hand, the N-terminal domain, although appearing to be well structured and in the hydrophobic core of the bilayer, has a broad range of orientations relative to the bilayer normal. The structure is not just half of the open-state dimer, and neither is the structure restricted to the surface of the bilayer. Consequently, the monomeric or closed state appears to be a hybrid of these two models from the literature.

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