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Please use this identifier to cite or link to this item: http://hdl.handle.net/11375/22766
Title: The Membrane-Mediated Conformation of Dynorphin A-(1-13)-Peptide as Studied by Nuclear Magnetic Resonance Spectroscopy, Circular Dichroism Spectropolarimetry, and Molecular Dynamics
Other Titles: The Membrane-Mediated Conformation of Dynorphin A-(1-13)
Authors: Lancaster, Charles
Advisor: Epand, R. M.
Department: Biochemistry
Keywords: dynorphin;peptide;dichroism;magnetic resonance
Publication Date: Sep-1990
Abstract: The structural requirements for the binding of dynorphin to the kappa opioid receptor are of profound clinical interest in the search for a powerful non-addictive analgesic. These requirements are thought to be met by the membrane-mediated conformation of the opioid peptide dynorphin A-(1-13}, Tyr¹-Gly²-Gly³-Phe⁴-Leu⁵-Arg⁶-Arg⁷-Ile⁸-Arg⁹-Pro¹⁰-Lys¹¹-Leu¹²-Lys¹³. Schwyzer [𝘉𝘪𝘰𝘤𝘩𝘦𝘮𝘪𝘴𝘵𝘳𝘺 25: 4281-4286 (1986)] has proposed an essentially α-helical membrane-mediated conformation of the tridecapeptide. In the present study, the hydrophobic moment, the helix probability and a four -state secondary structure prediction were computed. They signified, in agreement with circular dichroism (CD) studies on phospholipid-bound dynorphin A-(1-13)-tridecapeptide, negligible helical content of the peptide. CD studies demonstrated that the aqueous-membraneous interphase can be mimicked by methanol. The 500 and 620 MHz ¹H nuclear magnetic resonance (NMR) spectra of dynorphin A-(1-13) in methanolic solution were sequence-specifically assigned with the aid of correlated spectroscopy (COSY), double-quantum filtered phase-sensitive COSY, relayed COSY (RELAY) and nuclear Overhauser enhancement spectroscopy (NOESY). 2-D CAMELSPIN/ROESY experiments indicated that at least the part of the molecule from Arg⁷ to Arg⁹ was in an extended or β-strand conformation, which was in line with deuterium exchange and temperature dependence studies of the amide protons. ¹³C_α spin-lattice relaxation rate constants indicated a non-rigid backbone conformation. Transferred nuclear Overhauser effect studies on aqueous systems containing dynorphin A-(1-13) in the presence of dimyristoyl-phosphatidylcholine bilayers indicated a folded conformation from Tyr¹ to Leu⁵. The findings were incorporated into a tentative molecular model, which also indicated a non-helical, non-extended conformation for the rest of the molecule in the presence of corresponding distance-restrained negative charges.
URI: http://hdl.handle.net/11375/22766
Appears in Collections:Digitized Open Access Dissertations and Theses

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