Structure-activity relationships of endomorphin-1, endomorphin-2 and morphiceptin by molecular dynamics methods

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Abstract

A conformational analysis of endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2, EM1), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH2, MC), as μ-opioid receptor ligands was performed by the simulated annealing (SA) method and solvated molecular dynamics (MD) calculations. In SA experiments, 1000 conformers were generated for each peptide with both cis and trans Tyr-Pro peptide bond isomers. The populations of the conformers in the different regions of the Ramachandran plots and the numbers of the various types of turns and the distribution of distances of the main pharmacophore elements (i.e. phenolic OH of Tyr 1, tyramine N and the aromatic side-chain of Phe3) for the three peptides were compared. EM1 and EM2 seemed to be almost identical in their conformational features, ca. 30% of their conformers possessed turns with a significant ratio of β-turn type III, while in MC a drastic decrease in the number of turns and an increase of the number of extended structures were observed. According to the differences in the Φ33 Ramachandran plots, the Phe3 pharmacophore was affected in MC. Also, a pairwise comparison of the interaction energies between all fragments of the peptides (i.e. between backbone and side-chain fragments of each amino acid residue) showed that the presence of Pro4 in MC initiated increased repulsive interactions toward the Pro2-Phe 3 fragment relative to Phe4 toward the Pro 2-Phe3 and Pro2-Trp3 fragments in EM2 and EM1, respectively, accounting for its decreased opioid activity. The conformational analysis was repeated by isotherm molecular dynamics calculations in a periodic box with a modified GROMOS96 force field. The results support our previous experience.

Original languageEnglish
Pages (from-to)345-353
Number of pages9
JournalJournal of Molecular Structure: THEOCHEM
Volume666-667
DOIs
Publication statusPublished - dec. 29 2003

Fingerprint

Molecular Dynamics Simulation
Structure-Activity Relationship
Peptides
peptides
Molecular dynamics
fragments
molecular dynamics
Simulated annealing
beta-casomorphin 4
tyrosyl-proline
simulated annealing
Tyramine
Peptide Fragments
plots
Opioid Receptors
Isomers
Opioid Analgesics
Isotherms
field theory (physics)
Ligands

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computational Theory and Mathematics
  • Atomic and Molecular Physics, and Optics

Cite this

@article{7f038d785c754a03bbc5204238b8e18e,
title = "Structure-activity relationships of endomorphin-1, endomorphin-2 and morphiceptin by molecular dynamics methods",
abstract = "A conformational analysis of endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2, EM1), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH2, MC), as μ-opioid receptor ligands was performed by the simulated annealing (SA) method and solvated molecular dynamics (MD) calculations. In SA experiments, 1000 conformers were generated for each peptide with both cis and trans Tyr-Pro peptide bond isomers. The populations of the conformers in the different regions of the Ramachandran plots and the numbers of the various types of turns and the distribution of distances of the main pharmacophore elements (i.e. phenolic OH of Tyr 1, tyramine N and the aromatic side-chain of Phe3) for the three peptides were compared. EM1 and EM2 seemed to be almost identical in their conformational features, ca. 30{\%} of their conformers possessed turns with a significant ratio of β-turn type III, while in MC a drastic decrease in the number of turns and an increase of the number of extended structures were observed. According to the differences in the Φ3-Ψ 3 Ramachandran plots, the Phe3 pharmacophore was affected in MC. Also, a pairwise comparison of the interaction energies between all fragments of the peptides (i.e. between backbone and side-chain fragments of each amino acid residue) showed that the presence of Pro4 in MC initiated increased repulsive interactions toward the Pro2-Phe 3 fragment relative to Phe4 toward the Pro 2-Phe3 and Pro2-Trp3 fragments in EM2 and EM1, respectively, accounting for its decreased opioid activity. The conformational analysis was repeated by isotherm molecular dynamics calculations in a periodic box with a modified GROMOS96 force field. The results support our previous experience.",
keywords = "β-turns, Conformational analysis, Endomorphin-1, Endomorphin-2, Intramolecular H-bonds, Intramolecular interaction energy, Molecular dynamics, Morphiceptin, Regular and inverse γ-turns, Simulated annealing",
author = "F. {\"O}tv{\"o}s and T. K{\"o}rtv{\'e}lyesi and G{\'e}za T{\'o}th",
year = "2003",
month = "12",
day = "29",
doi = "10.1016/j.theochem.2003.08.044",
language = "English",
volume = "666-667",
pages = "345--353",
journal = "Computational and Theoretical Chemistry",
issn = "2210-271X",
publisher = "Elsevier BV",

}

TY - JOUR

T1 - Structure-activity relationships of endomorphin-1, endomorphin-2 and morphiceptin by molecular dynamics methods

AU - Ötvös, F.

AU - Körtvélyesi, T.

AU - Tóth, Géza

PY - 2003/12/29

Y1 - 2003/12/29

N2 - A conformational analysis of endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2, EM1), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH2, MC), as μ-opioid receptor ligands was performed by the simulated annealing (SA) method and solvated molecular dynamics (MD) calculations. In SA experiments, 1000 conformers were generated for each peptide with both cis and trans Tyr-Pro peptide bond isomers. The populations of the conformers in the different regions of the Ramachandran plots and the numbers of the various types of turns and the distribution of distances of the main pharmacophore elements (i.e. phenolic OH of Tyr 1, tyramine N and the aromatic side-chain of Phe3) for the three peptides were compared. EM1 and EM2 seemed to be almost identical in their conformational features, ca. 30% of their conformers possessed turns with a significant ratio of β-turn type III, while in MC a drastic decrease in the number of turns and an increase of the number of extended structures were observed. According to the differences in the Φ3-Ψ 3 Ramachandran plots, the Phe3 pharmacophore was affected in MC. Also, a pairwise comparison of the interaction energies between all fragments of the peptides (i.e. between backbone and side-chain fragments of each amino acid residue) showed that the presence of Pro4 in MC initiated increased repulsive interactions toward the Pro2-Phe 3 fragment relative to Phe4 toward the Pro 2-Phe3 and Pro2-Trp3 fragments in EM2 and EM1, respectively, accounting for its decreased opioid activity. The conformational analysis was repeated by isotherm molecular dynamics calculations in a periodic box with a modified GROMOS96 force field. The results support our previous experience.

AB - A conformational analysis of endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2, EM1), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM2) and morphiceptin (Tyr-Pro-Phe-Pro-NH2, MC), as μ-opioid receptor ligands was performed by the simulated annealing (SA) method and solvated molecular dynamics (MD) calculations. In SA experiments, 1000 conformers were generated for each peptide with both cis and trans Tyr-Pro peptide bond isomers. The populations of the conformers in the different regions of the Ramachandran plots and the numbers of the various types of turns and the distribution of distances of the main pharmacophore elements (i.e. phenolic OH of Tyr 1, tyramine N and the aromatic side-chain of Phe3) for the three peptides were compared. EM1 and EM2 seemed to be almost identical in their conformational features, ca. 30% of their conformers possessed turns with a significant ratio of β-turn type III, while in MC a drastic decrease in the number of turns and an increase of the number of extended structures were observed. According to the differences in the Φ3-Ψ 3 Ramachandran plots, the Phe3 pharmacophore was affected in MC. Also, a pairwise comparison of the interaction energies between all fragments of the peptides (i.e. between backbone and side-chain fragments of each amino acid residue) showed that the presence of Pro4 in MC initiated increased repulsive interactions toward the Pro2-Phe 3 fragment relative to Phe4 toward the Pro 2-Phe3 and Pro2-Trp3 fragments in EM2 and EM1, respectively, accounting for its decreased opioid activity. The conformational analysis was repeated by isotherm molecular dynamics calculations in a periodic box with a modified GROMOS96 force field. The results support our previous experience.

KW - β-turns

KW - Conformational analysis

KW - Endomorphin-1

KW - Endomorphin-2

KW - Intramolecular H-bonds

KW - Intramolecular interaction energy

KW - Molecular dynamics

KW - Morphiceptin

KW - Regular and inverse γ-turns

KW - Simulated annealing

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U2 - 10.1016/j.theochem.2003.08.044

DO - 10.1016/j.theochem.2003.08.044

M3 - Article

AN - SCOPUS:1642574354

VL - 666-667

SP - 345

EP - 353

JO - Computational and Theoretical Chemistry

JF - Computational and Theoretical Chemistry

SN - 2210-271X

ER -