Comparative conformational analyses of μ-selective dermorphin and §-selective deltorphin-II in aqueous solution by 1H-NMR spectroscopy

Two-dimensional ¹H-NMR methods have been used to obtain complete proton resonance assignments and possible solution conformations of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH₂) and deltorphin-II (H-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH₂), naturally occurring μ and §-selective opioids, respectively, in order to examine the conformational characteristics that are closely related to the selectivities towards μ/§ opioid receptors. With the use of the proton-proton distances derived from ROESY measurements in aqueous solution, 50 possible 3D structures are generated by means of distance geometry calculations. The conformers which satisfy the distance constraints and the torsion angles estimated from J_NHCxH vicinal coupling constants within the allowable range are then subjected to molecular dynamics simulations for 10 ps after equilibration. Although dermorphin and deltorphin-II are both in equilibrium among many flexible conformers, some conformational differences are observed between these peptides: many conformers of dermorphin show a structure rounded at the N-terminal Tyr-D-Ala-Phe-Gly-Tyr and C-terminal Gly-Tyr-Pro-Ser-NH₂ moieties, which are almost at right angles to each other, while those of deltorphin-II are characterized by a ‘hook’ -shaped backbone structure in which the nearly extended conformation of the Val-Val-Gly-NH₂ sequence is located under the folded conformation of the N-terminal Tyr-D-Ala-Phe-Glu sequence. The possible relationship between these conformational characteristics and the μ/§-opioid receptor selectivities is discussed.