Dermenkephalin (DRE, H-Tyr-D-Met-Phe-His-Leu-Met-Asp-NH2), a natural peptide found in frog skin, has high potency and receptor selectivity for δ opioid receptors and has potent in vivo analgesic activity. Structurally the compound is related to both the μ opioid receptor selective dermorphin and the δ opioid receptor selective deltorphins. Interestingly, the N-terminal tetrapeptide of DRE is potent and selective for the μ opioid receptor. Efforts to understand the conformational properties of DRE and their relationships to biological activity are of great importance. We report here a novel approach to analyze conformations of short linear peptides in solution to determine the possible solution conformations of DRE. We have combined extensive NMR studies with comprehensive conformational energy calculations, including extensive Monte Carlo sampling and statistical evaluations of the results, to obtain the statistical weight estimations for DRE low-energy backbone conformations that are consistent with all of the NMR data. A random search of conformer statistical weights was performed to satisfy the condition of statistical indistinguishability between the experimental values and the weighted sum of calculated values for each measured parameter. From these studies, two low-energy conformers were found to be essential for matching the energy calculation results with the NMR data. At least one of them should be present among the DRE solution conformers with a significant statistical weight. Except for the rotamers of the side chain groups of the Tyr1 and Phe3 residues, the conformations of the N-terminal tripeptide fragment match in detail a previously suggested topographical model for the conformation responsible for interaction with the δ opioid receptor. This suggests that the δ selectivity of DRE, which is a linear flexible peptide, might be due to pre-existence in solution of a specific conformer for its N-terminal tripeptide. The combined approach employed in this study offers a useful methodology to aid in conformational analysis of linear, conformationally flexible peptides that are active at receptors and other biological important acceptors.
|Original language||English (US)|
|Journal||Journal of the American Chemical Society|
|State||Published - May 5 1993|
ASJC Scopus subject areas
- Colloid and Surface Chemistry