The mu-selective heptapeptide opioid dermorphin has two conformations around Phe3 psi with no head-to-tail interaction. A quantitative 2-D NMR and molecular modeling analysis.

The mu opioid heptapeptide Dermorphin (DRM) is under 70 % of trans forms for the Tyr(5)-Pro(6) peptide bond in solution (CDCl(3)/DMSO-d(6) 1/1 vol/vol). Variations of NOE integrals at 5 temperatures show apparent correlation times of 0.8 to 0.9 ns (at 280 K) in that mixed solvent. Four NOE between non-adjacent residues reveal a large population of folded structures. However, in trans DRM, 4 adjacent NOE Phe(3)/Gly(4) can only be explained by an equilibrium between folded (psi(3) > 0) and extended (psi(3) > 0) conformations. Simulated annealing modeling gave about 60% (psi(3) > 0) and 40% (psi(3) > 0) of these conformer populations. Trans DRM study and previous studies on the heptapeptide opioids, dermenkephalin (DREK) and deltorphin-I (delta selective), and DREK(1-4)-DRM(5-7) hybrid (mu selective), show in folded structures more backbone bending of the first 4 residues in the mu opioids than in the delta peptides. Also, the main difference between mu- and delta-opioid peptides is a large fraction of extended conformations in mu heptapeptides. Either bending of the N-terminus, or extension of the C-terminal part in mu-opioid heptapeptides prevent the head-to-tail interactions which allow delta-opioid peptides to bind selectively to the delta-opioid receptor.