Conformational analysis of the LBQ 83–99 (Phe 91 ) and LBQ 83–99 (Tyr 91 ) peptide analogues and study of their interactions with the HLA-DR2 and human TCR receptors by using Molecular Dynamics C. Potamitis • M.-T. Matsoukas • T. Tselios • T. Mavromoustakos • S. Golic ˇ Grdadolnik Received: 10 September 2010 / Accepted: 17 August 2011 / Published online: 6 September 2011 Ó Springer Science+Business Media B.V. 2011 Abstract The two new synthetic analogues of the MBP 83–99 epitope substituted at Lys 91 (primary TCR con- tact) with Phe [MBP 83–99 (Phe 91 )] or Tyr [MBP 83–99 (Tyr 91 )], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been per- formed 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 MBP 83–99 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 con- formational characteristics of the MBP 83–99 immunodomi- nant 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. Keywords Molecular Dynamics (MD) Á Myelin basic protein (MBP) Á Conformational analysis Á Binding motif Á NMR Á Multiple sclerosis (MS) Introduction Multiple sclerosis (MS) is an inflammatory disease, char- acterized by the demyelination of the white matter of the central nervous system (CNS). It is caused by aberrant responses of autoreactive T-cells that escape negative selection [1, 2]. T-cell receptors (TCRs) recognize self- peptide fragments bound to major histocompatibility complex II (MHC II) molecules (in human referred to as HLA, Human Leukocyte Antigens). This recognition results in T-cell activation and proliferation and the trig- gering of an autoimmune response [3, 4]. It is well known that MBP epitopes induce in mice experimental autoim- mune encephalomyelitis (EAE), the best studied animal model of MS [7, 8, 10, 11, 12]. Reported work has demonstrated that the HLA-DR2 (DRA, DRB1*1501) haplotype is present at an increased Electronic supplementary material The online version of this article (doi:10.1007/s10822-011-9467-4) contains supplementary material, which is available to authorized users. C. Potamitis Á T. Mavromoustakos National Hellenic Research Foundation, Institute of Organic and Pharmaceutical Chemistry, Vas. Constantinou 48, 11635 Athens, Greece C. Potamitis Á T. Mavromoustakos (&) Chemistry Department, University of Athens, Panepistimiopolis, Zographou, 15784 Athens, Greece e-mail: tmavrom@chem.uoa.gr M.-T. Matsoukas Á T. Tselios (&) Department of Chemistry, University of Patras, Patras 26500, Greece e-mail: ttselios@upatras.gr S. Golic ˇ Grdadolnik Laboratory of Biomolecular Structure, National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia S. Golic ˇ Grdadolnik (&) EN-FIST Centre of Excellence, Dunajska 156, 1000 Ljubljana, Slovenia e-mail: simona.grdadolnik@ki.si 123 J Comput Aided Mol Des (2011) 25:837–853 DOI 10.1007/s10822-011-9467-4