Structural Model of a Cyclic Dynorphin A Analog Bound to Dodecylphosphocholine Micelles by NMR and Restrained Molecular Dynamics

Abstract

The compound c[Cys5,11]dynorphin A-(1-11)-NH2, 1, is a cyclic dynorphin A analog that shows similar selectivity and potency at the kappa-opioid receptor when compared to the native form of the peptide in central nervous system assays. Previous molecular mechanics calculations have shown that the ring portion of the isoform that is trans about the Arg9-Pro10 omega bond contains either a beta-turn from residues Arg6 to Arg9 or an alpha-helical conformation. Our results from solution state NMR indicate that the compound exhibits cis-trans isomerism about the Arg9-Pro10 omega bond in both aqueous solution and when bound to dodecylphosphocholine micelles. Restrained molecular dynamics calculations show that the cis isoform of the peptide contains a type III beta-turn from residues Arg7 to Pro10. Similar calculations on the trans isoform show it to contain a beta-turn from residues Cys5 and Arg8. In this report we describe the generation of three-dimensional models from NMR data for the ring portions of both the cis and trans isoforms of 1 bound to dodecylphosphocholine micelles. Comparison with other dynorphin A structural information indicates that both the cis and trans isoforms of the peptide may be active as kappa-opioid agonists.

Solution structure of nociceptin peptides

“…Opioid peptides have often been studied in media similar to the membrane environment, usually aqueous micellar solutions. The micelles generally used are based on SDS, a detergent easy to find in perdeuterated form [26][27][28][29], but there are also published studies of micelles of phospholipids [30][31][32][33][34][35][36].…”

NMR studies of adrenocorticotropin hormone peptides in sodium dodecylsulfate and dodecylphosphocholine micelles: Proline isomerism and interactions of the peptides with micelles

“…In bovine prothrombin, it was found that the cis X-Pro 22 conformer is essential to creating the membrane-binding conformation of prothrombin. 13,14 Tessmer et al 36 showed that for a cyclic dynorphin A analogue, the interaction with the DPC micelles stabilized the trans proline isomer (Arg-Pro). This is contrary to our result that shows that DPC does not affect the trans-cis equilibrium in the 11-24 segment of ACTH.…”

Conformational analysis of the endogenous μ‐opioid agonist endomorphin‐1 using NMR spectroscopy and molecular modeling

“…Identification and structural characterization of selective opioid peptide ligands for the δ receptor (e.g. DPDPE [11], JOM‐13 [12]) and the κ receptor (dynorphin [13, 14]) have allowed modeling studies to begin for these types, but to date, few such studies for μ‐selective peptide ligands ( d ‐TIPP‐NH 2 ) have been reported [15].…”