Conformational analysis of βmethyl-para-nitrophenylalanine stereoisomers of cyclo[D-Pen2, D-Pen5]enkephalin by NMR spectroscopy and conformational energy calculations

Mark D. Shenderovich, Katalin E. Kövér, Gregory V. Nikiforovich, Ding Jiao, Victor J Hruby

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Abstract

Solution conformations of β-methyl-para-nitrophenylalanine4 analogues of the potent δ-opioid peptide cyclo[ D-Pen2, D-Pen5 ] enkephalin (DPDPE) were studied by combined use of nmr and conformational energy calculations. Nuclear Overhauser effect connectivities and 3JHNCαH coupling constants measured for the (2S, 3S)-, (2S, 3R)-, and (2R, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE in DMSO were compared with low energy conformer obtained by energy minimization in the Empirical Conformational Energy Program for Peptides (ECEPP/2) force field. The conformers that satisfied all available nmr data were selected as probable solution conformations of these peptides. Side-chain rotamer populations, established using homo-nuclear (3JHαHβ) and heteronuclear (3JHαCγ) coupling constants and 13C chemical shifts, show that the β-methyl substituent eliminates one of the three staggered rotamers of the torsion angle X1for each stereoisomer of the β-Me-p-NO2Phe4. Similar solution conformations were suggested for the L-Phe4-containing (2S, 3S)- and (2S, 3R)-stereoisomers. Despite some local differences, solution conformations of L- and D-Phe4-containing analogues have a common shape of the peptide backbone and allow similar orientations of the main δ-opioid pharmacophores. This type of structure differs from several models of the solution conformations of DPDPE, and from the model of biologically active conformations of DPDPE suggested earlier. The latter model is allowed for the potent (2S, 3S)- and (2S, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE, but it is forbidden for the less active (2R, 3R)- and (2R, 3S)-stereoisomers. It was concluded that the biologically active stereoisomers of [ β-Me-p-NO2Phe4]DPDPE in the δ-receptor-bound state may assume a conformation different from their favorable conformations in DMSO.

Original languageEnglish (US)
Pages (from-to)141-156
Number of pages16
JournalBiopolymers - Peptide Science Section
Volume38
Issue number2
StatePublished - 1996

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D-Penicillamine (2,5)-Enkephalin
Stereoisomerism
Nuclear magnetic resonance spectroscopy
Conformations
Magnetic Resonance Spectroscopy
Peptides
Dimethyl Sulfoxide
Opioid Peptides
Opioid Receptors
Opioid Analgesics
Chemical shift
Torsional stress
Population

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Biochemistry
  • Biophysics

Cite this

Conformational analysis of βmethyl-para-nitrophenylalanine stereoisomers of cyclo[D-Pen2, D-Pen5]enkephalin by NMR spectroscopy and conformational energy calculations. / Shenderovich, Mark D.; Kövér, Katalin E.; Nikiforovich, Gregory V.; Jiao, Ding; Hruby, Victor J.

In: Biopolymers - Peptide Science Section, Vol. 38, No. 2, 1996, p. 141-156.

Research output: Contribution to journalArticle

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title = "Conformational analysis of βmethyl-para-nitrophenylalanine stereoisomers of cyclo[D-Pen2, D-Pen5]enkephalin by NMR spectroscopy and conformational energy calculations",
abstract = "Solution conformations of β-methyl-para-nitrophenylalanine4 analogues of the potent δ-opioid peptide cyclo[ D-Pen2, D-Pen5 ] enkephalin (DPDPE) were studied by combined use of nmr and conformational energy calculations. Nuclear Overhauser effect connectivities and 3JHNCαH coupling constants measured for the (2S, 3S)-, (2S, 3R)-, and (2R, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE in DMSO were compared with low energy conformer obtained by energy minimization in the Empirical Conformational Energy Program for Peptides (ECEPP/2) force field. The conformers that satisfied all available nmr data were selected as probable solution conformations of these peptides. Side-chain rotamer populations, established using homo-nuclear (3JHαHβ) and heteronuclear (3JHαCγ) coupling constants and 13C chemical shifts, show that the β-methyl substituent eliminates one of the three staggered rotamers of the torsion angle X1for each stereoisomer of the β-Me-p-NO2Phe4. Similar solution conformations were suggested for the L-Phe4-containing (2S, 3S)- and (2S, 3R)-stereoisomers. Despite some local differences, solution conformations of L- and D-Phe4-containing analogues have a common shape of the peptide backbone and allow similar orientations of the main δ-opioid pharmacophores. This type of structure differs from several models of the solution conformations of DPDPE, and from the model of biologically active conformations of DPDPE suggested earlier. The latter model is allowed for the potent (2S, 3S)- and (2S, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE, but it is forbidden for the less active (2R, 3R)- and (2R, 3S)-stereoisomers. It was concluded that the biologically active stereoisomers of [ β-Me-p-NO2Phe4]DPDPE in the δ-receptor-bound state may assume a conformation different from their favorable conformations in DMSO.",
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T1 - Conformational analysis of βmethyl-para-nitrophenylalanine stereoisomers of cyclo[D-Pen2, D-Pen5]enkephalin by NMR spectroscopy and conformational energy calculations

AU - Shenderovich, Mark D.

AU - Kövér, Katalin E.

AU - Nikiforovich, Gregory V.

AU - Jiao, Ding

AU - Hruby, Victor J

PY - 1996

Y1 - 1996

N2 - Solution conformations of β-methyl-para-nitrophenylalanine4 analogues of the potent δ-opioid peptide cyclo[ D-Pen2, D-Pen5 ] enkephalin (DPDPE) were studied by combined use of nmr and conformational energy calculations. Nuclear Overhauser effect connectivities and 3JHNCαH coupling constants measured for the (2S, 3S)-, (2S, 3R)-, and (2R, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE in DMSO were compared with low energy conformer obtained by energy minimization in the Empirical Conformational Energy Program for Peptides (ECEPP/2) force field. The conformers that satisfied all available nmr data were selected as probable solution conformations of these peptides. Side-chain rotamer populations, established using homo-nuclear (3JHαHβ) and heteronuclear (3JHαCγ) coupling constants and 13C chemical shifts, show that the β-methyl substituent eliminates one of the three staggered rotamers of the torsion angle X1for each stereoisomer of the β-Me-p-NO2Phe4. Similar solution conformations were suggested for the L-Phe4-containing (2S, 3S)- and (2S, 3R)-stereoisomers. Despite some local differences, solution conformations of L- and D-Phe4-containing analogues have a common shape of the peptide backbone and allow similar orientations of the main δ-opioid pharmacophores. This type of structure differs from several models of the solution conformations of DPDPE, and from the model of biologically active conformations of DPDPE suggested earlier. The latter model is allowed for the potent (2S, 3S)- and (2S, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE, but it is forbidden for the less active (2R, 3R)- and (2R, 3S)-stereoisomers. It was concluded that the biologically active stereoisomers of [ β-Me-p-NO2Phe4]DPDPE in the δ-receptor-bound state may assume a conformation different from their favorable conformations in DMSO.

AB - Solution conformations of β-methyl-para-nitrophenylalanine4 analogues of the potent δ-opioid peptide cyclo[ D-Pen2, D-Pen5 ] enkephalin (DPDPE) were studied by combined use of nmr and conformational energy calculations. Nuclear Overhauser effect connectivities and 3JHNCαH coupling constants measured for the (2S, 3S)-, (2S, 3R)-, and (2R, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE in DMSO were compared with low energy conformer obtained by energy minimization in the Empirical Conformational Energy Program for Peptides (ECEPP/2) force field. The conformers that satisfied all available nmr data were selected as probable solution conformations of these peptides. Side-chain rotamer populations, established using homo-nuclear (3JHαHβ) and heteronuclear (3JHαCγ) coupling constants and 13C chemical shifts, show that the β-methyl substituent eliminates one of the three staggered rotamers of the torsion angle X1for each stereoisomer of the β-Me-p-NO2Phe4. Similar solution conformations were suggested for the L-Phe4-containing (2S, 3S)- and (2S, 3R)-stereoisomers. Despite some local differences, solution conformations of L- and D-Phe4-containing analogues have a common shape of the peptide backbone and allow similar orientations of the main δ-opioid pharmacophores. This type of structure differs from several models of the solution conformations of DPDPE, and from the model of biologically active conformations of DPDPE suggested earlier. The latter model is allowed for the potent (2S, 3S)- and (2S, 3R)-stereoisomers of [β-Me-pNO2Phe4]DPDPE, but it is forbidden for the less active (2R, 3R)- and (2R, 3S)-stereoisomers. It was concluded that the biologically active stereoisomers of [ β-Me-p-NO2Phe4]DPDPE in the δ-receptor-bound state may assume a conformation different from their favorable conformations in DMSO.

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