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Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics

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Abstract

The two new synthetic analogues of the MBP83–99 epitope substituted at Lys91 (primary TCR contact) with Phe [MBP83–99 (Phe91)] or Tyr [MBP83–99 (Tyr91)], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP83–99 epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP83–99 immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes.

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Acknowledgments

This work was partially supported by EN-FIST Centre of Excellence (Dunajska 156, SI-1000 Ljubljana, Slovenia) and Ministry of Higher Education, Science and Technology of Slovenia. We acknowledge A. Suarez amd M. Mavromoustakos for their linguistic amendment of the manuscript. We gratefully thank Prof. Leonardo Pardo (Universitat Autόnoma de Barcelona) for computer facilities and software use.

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Authors and Affiliations

  1. National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Vas. Constantinou 48, 11635, Athens, Greece

    C. Potamitis & T. Mavromoustakos

  2. Chemistry Department, University of Athens, Panepistimiopolis, Zographou, 15784, Athens, Greece

    C. Potamitis & T. Mavromoustakos

  3. Department of Chemistry, University of Patras, Patras, 26500, Greece

    M.-T. Matsoukas & T. Tselios

  4. Laboratory of Biomolecular Structure, National Institute of Chemistry, Hajdrihova 19, 1001, Ljubljana, Slovenia

    S. Golič Grdadolnik

  5. EN-FIST Centre of Excellence, Dunajska 156, 1000, Ljubljana, Slovenia

    S. Golič Grdadolnik

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  1. C. Potamitis
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  2. M.-T. Matsoukas
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  3. T. Tselios
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  4. T. Mavromoustakos
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Correspondence to T. Tselios, T. Mavromoustakos or S. Golič Grdadolnik.

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10822_2011_9467_MOESM1_ESM.doc

Tables of 1H and 13C chemical shifts, NMR spectra of two new synthetic analogues of the MBP83–99 epitope substituted at Lys91 amino acid with Phe (MBP83–99 (Phe91)) or Tyr (MBP83–99 (Tyr91)) (DOC 6909 kb)

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Potamitis, C., Matsoukas, MT., Tselios, T. et al. Conformational analysis of the ΜΒΡ83–99 (Phe91) and ΜΒΡ83–99 (Tyr91) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics. J Comput Aided Mol Des 25, 837–853 (2011). https://doi.org/10.1007/s10822-011-9467-4

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