Homology modeling and molecular dynamics simulations of MUC1-9/H-2K b complex suggest novel binding interactions

Athanassios Stavrakoudis, Ioannis G. Tsoulos, K. Uray, F. Hudecz, Vasso Apostolopoulos

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Human MUC1 is over-expressed in human adenocarcinomas and has been used as a target for immunotherapy studies. The 9-mer MUC1-9 peptide has been identified as one of the peptides which binds to murine MHC class I H-2Kb. The structure of MUC1-9 in complex with H-2Kb has been modeled and simulated with classical molecular dynamics, based on the x-ray structure of the SEV9 peptide/H-2Kb complex. Two independent trajectories with the solvated complex (10 ns in length) were produced. Approximately 12 hydrogen bonds were identified during both trajectories to contribute to peptide/MHC complex, as well as 1-2 water mediated hydrogen bonds. Stability of the complex was also confirmed by buried surface area analysis, although the corresponding values were about 20% lower than those of the original x-ray structure. Interestingly, a bulged conformation of the peptide's central region, partially characterized as a β-turn, was found exposed form the binding groove. In addition, P1 and P9 residues remained bound in the A and F binding pockets, even though there was a suggestion that P9 was more flexible. The complex lacked numerous water mediated hydrogen bonds that were present in the reference peptide x-ray structure. Moreover, local displacements of residues Asp4, Thr5 and Pro9 resulted in loss of some key interactions with the MHC molecule. This might explain the reduced affinity of the MUC1-9 peptide, relatively to SEV9, for the MHC class I H-2Kb.

Original languageEnglish
Pages (from-to)1817-1829
Number of pages13
JournalJournal of Molecular Modeling
Volume17
Issue number7
DOIs
Publication statusPublished - Jul 2011

Fingerprint

homology
Peptides
peptides
Molecular dynamics
molecular dynamics
Computer simulation
simulation
interactions
Hydrogen bonds
hydrogen bonds
X rays
Trajectories
trajectories
x rays
Water
grooves
water
suggestion
affinity
Conformations

Keywords

  • Class I MHC
  • H-2K
  • Homology modeling
  • Molecular dynamics
  • MUC1
  • Tumor

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Computer Science Applications
  • Computational Theory and Mathematics
  • Catalysis
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Homology modeling and molecular dynamics simulations of MUC1-9/H-2K b complex suggest novel binding interactions. / Stavrakoudis, Athanassios; Tsoulos, Ioannis G.; Uray, K.; Hudecz, F.; Apostolopoulos, Vasso.

In: Journal of Molecular Modeling, Vol. 17, No. 7, 07.2011, p. 1817-1829.

Research output: Contribution to journalArticle

Stavrakoudis, Athanassios ; Tsoulos, Ioannis G. ; Uray, K. ; Hudecz, F. ; Apostolopoulos, Vasso. / Homology modeling and molecular dynamics simulations of MUC1-9/H-2K b complex suggest novel binding interactions. In: Journal of Molecular Modeling. 2011 ; Vol. 17, No. 7. pp. 1817-1829.
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