title: Comparison of the membrane-bound states of two structurally similar delta-selective opioid peptides by transferred nuclear Overhauser effect spectroscopy and molecular modeling.
abstract: 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 (TRNOE) was used to obtain NOE profiles of the free and membrane bound forms of DPDPE and acyclic DPDPE. After comparison of the profiles of both peptides in the free and membrane-bound states, we hypothesize that 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 groups were observed after interaction with the membrane. Results of computerized molecular modeling studies also were consistent with our theory that the free and membrane-bound forms of cyclic DPDPE have very similar free and membrane-bound states. The free acyclic DPDPE has a reverse turn conformation with sidechains situated so that hydrophobic surface exposure to aqueous solution is minimized. After membrane interaction, the acyclic DPDPE has an extended conformation near the carboxy terminus with aromatic sidechains widely separated. We propose that the interaction of the acyclic DPDPE with the membrane surface is mediated by the amino terminus. We further propose that the interaction of the cyclic DPDPE with the membrane surface is limited because the D-Pen2 side chain is covalently bonded and the aromatic side chains and backbone are only slightly altered after membrane contact. Permeability studies by Ramaswami et al. [(1992) Biochim. Biophys. Acta 1109(2), 195-202] demonstrated that the acyclic DPDPE permeated through membranes at a rate 4 times greater than cyclic DPDPE. We conclude that conformational and topographical flexibility may be critical factors in peptide-membrane interactions and permeability of bilayer membranes to opioid peptides.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson 85721.
authors.forename: T O
authors.initials: TO
authors.lastname: Matsunaga
authors.forename: N
authors.initials: N
authors.lastname: Collins
authors.forename: V
authors.initials: V
authors.lastname: Ramaswami
authors.forename: S H
authors.initials: SH
authors.lastname: Yamamura
authors.forename: D F
authors.initials: DF
authors.lastname: O'Brien
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
mesh_terms: D002462:Cell Membrane / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry*; D066298:In Vitro Techniques; D008024:Ligands; D008027:Light; D008081:Liposomes; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017465:Receptors, Opioid, delta / Q000737:chemistry / Q000378:metabolism; D012542:Scattering, Radiation; D012996:Solutions; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014783:Viscosity
chemical_list: D004745:Enkephalins; D008024:Ligands; D008081:Liposomes; D017465:Receptors, Opioid, delta; D012996:Solutions; D020881:Enkephalin, D-Penicillamine (2,5)-