COMPARISON OF THE MEMBRANE-BOUND STATES OF 2 STRUCTURALLY SIMILAR DELTA-SELECTIVE OPIOID-PEPTIDES BY TRANSFERRED NUCLEAR OVERHAUSER EFFECT SPECTROSCOPY AND MOLECULAR MODELING

NMR spectroscopic, peptide-membrane conformational studies on [D-Pen2, D-Pen5]-enkephalin (DPDPE), an opioid receptor selective peptide, and an acyclic analog of DPDPE (DPDPE reduced at the disulfide bond) were conducted. The NMR method of transferred nuclear Overhauser effect (T RNOE) was used to obtain NOE profiles of the free and membrane bound f orms of DPDPE and acyclic DPDPE. After comparison of the profiles of b oth peptides in the free and membrane-bound states, we hypothesize tha t the cyclic DPDPE undergoes little if any conformational change upon interaction with the membrane. However, for the acyclic analog, large changes in the NOE profile associated with backbone and side-chain gro ups were observed after interaction with the membrane. Results of comp uterized molecular modeling studies also were consistent with our theo ry that the free and membrane-bound forms of cyclic DPDPE have very si milar free and membrane-bound states. The free acyclic DPDPE has a rev erse turn conformation with sidechains situated so that hydrophobic su rface exposure to aqueous solution is minimized. After membrane intera ction, the acyclic DPDPE has an extended conformation near the carboxy terminus with aromatic sidechains widely separated. We propose that t he interaction of the acyclic DPDPE with the membrane surface is media ted by the amino terminus. We further propose that the interaction of the cyclic DPDPE with the membrane surface is limited because the D-Pe n2 side chain is covalently bonded and the aromatic side chains and ba ckbone are only slightly altered after membrane contact. Permeability studies by Ramaswami et al. [(1992) Biochim. Biophys. Acta 1109(2), 19 5-202] demonstrated that the acyclic DPDPE permeated through membranes at a rate 4 times greater than cyclic DPDPE. We conclude that conform ational and topographical flexibility may be critical factors in pepti de-membrane interactions and permeability of bilayer membranes to opio id peptides.