Conformation of deltorphin‐II in membrane environment studied by two‐dimensional NMR spectroscopy and molecular dynamics calculations

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Abstract
Two‐dimensional homonuclear Hartmann‐Hahn spectroscopy and NOESY (nuclear Overhauser effect and exchange spectroscopy) 1H‐NMR techniques have been used to obtain complete proton resonance assignments and to perform a conformational investigation of deltorphin‐II (Tyr‐D‐Ala‐Phe‐Glu‐Val‐Val‐Gly‐NH2), a naturally occurring δ‐selective opioid peptide, in the membrane‐mi‐metic micelles of perdeuterated dodecylphosphocholine. This was done in order to examine conformational characteristics that would be closely related to the selectivity towards the δ‐opioid receptor. With the use of the proton‐proton distances derived from NOESY measurements, 50 possible three‐dimensional structures were generated by means of distance‐geometry calculations, and 25 of them were subjected to the molecular‐dynamics simulations of 10 ps, which were energetically constrained for the NOE interproton distances. Most of the possible conformers simulated showed a common feature such that the conformation of deltorphin‐II is characterized by the S‐shaped back‐bone structure in which the turn conformation of the Val‐Val‐Gly‐NH2 sequence is located under the helically folded conformation of the N‐terminal Tyr‐D‐Ala‐Phe‐Glu sequence. The possible relationship between this conformational characteristic and the δ‐opioid‐receptor selectivity has been discussed.