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Proceedings of the 31 st European Peptide SymposiumMichal Lebl, Morten Meldal, Knud J. Jensen, Thomas Hoeg-Jensen (Editors)European Peptide Society, 2010VCD Spectroscopic Analysis of μ-Opioid PeptidesAttila Borics 1 , Géza Tóth 1 , and Sándor Lovas 21 Institute of Biochemistry, Biological Research Center of the Hungarian Academy ofSciences, Szeged, H-6726, Hungary; 2 Department of Biomedical Sciences, CreightonUniversity Medical Center, Omaha, NE, 68178, U.S.A.IntroductionThe determination of structural requirements of binding to the μ-opioid receptor is a keyaspect of the development of novel analgesics. Many natural and synthetic peptides andpeptidomimetics bind to the μ-opioid receptor with high affinity and selectivity, but there isno consensus about what is the structural requirement for such biological activity [1,2].Previously, ten μ-opioid receptor ligands (Table 1), including β-amino acid [3] or β-turninducing pseudo-dipeptide [4] containing endomorphin-1 and 2 (EM-1, EM-2) analogues,possessing different affinity and selectivity were examined using molecular dynamics(MD) in aqueous and dimethyl sulfoxide (DMSO) environment. Four structural parameterswere found to correlate with receptor binding data [5]. In the present study, IR and VCDspectroscopies were applied to determine the solution structure of these molecules.Theoretical simulation of the vibrational spectra of EM-1, utilizing quantum chemicalcalculations, was carried out using conformational data obtained from a previous MDsimulation. In this approach the theoretical spectra is built from spectra calculated for therepresentative structures of dominant conformational families. The effect of explicitlyincluded solvent molecules on the quantum chemical spectrum calculations wasinvestigated as well.Table 1. μ-Opioid receptor ligands addressed in this studySequenceReceptor affinity(K iμ/ nM)μ/δ selectivity(K i δ /K i μ )1 H-Tyr-Pro-Trp-Phe-NH 2 0-10 >10002 H-Tyr-Pro-Phe-Phe-NH 2 0-10 >10003 H-Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol 0-10 1000-1004 H-Tyr-(1S2R)-ACHC-Phe-Phe-NH 2 0-10 1000-1005 H-Tyr-Pro-Trp-Gly-NH 2 10-100 1000-1006 H-Tyr-(R)-spiro-Aba-Gly-Phe-NH 2 10-100 >10007 H-Tyr-Pro-Phe-Pro-NH 2 10-100 1000-1008 H-Tyr-(1R2R)-ACPC-Trp-Phe-NH 2 10-100 100-109 H-Tyr-(1R2S)-ACHC-Phe-Phe-NH 2 100-1000 >100010 H-Tyr-(R)-spiro-Aba-Gly-Phe-NH 2 100-1000