NMR and molecular dynamics studies of an autoimmune myelin basic protein peptide and its antagonist: Structural implications for the MHC II (I-A u)-peptide complex from docking calculations
Tzakos, Andreas G.; Fuchs, Patrick; Van Nuland, Nico A. J.; Troganis, Anastasios; Tselios, Theodore; Deraos, Spyros; Matsoukas, John; Gerothanassis, Ioannis P.; Bonvin, Alexandre M. J. J.
(2004) European Journal of Biochemistry, volume 271, issue 16, pp. 3399 - 3413
(Article)
Abstract
Experimental autoimmune encephalomyelitis can be induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP). To characterize the molecular features of antigenic sites important for designing experimental autoimmune encephalomyelitis suppressing molecules, we report structural studies, based on NMR experimental data in conjunction with molecular dynamic simulations, of the
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potent linear dodecapeptide epitope of guinea pig MBP, Gln74-Lys75-Ser76-Gln77-Arg78-Ser79-Gln80-Asp81-Glu82-Asn83-Pro84-Val85 [MBP(74-85)], and its antagonist analogue Ala81MBP(74-85). The two peptides were studied in both water and Me2SO in order to mimic solvent-dependent structural changes in MBP. The agonist MBP(74-85) adopts a compact conformation because of electrostatic interactions of Arg78 with the side chains of Asp81 and Glu82. Arg78 is 'locked' in a well-defined conformation, perpendicular to the peptide backbone which is practically solvent independent. These electrostatic interactions are, however, absent from the antagonist Ala81MBP(74-85), resulting in great flexibility of the side chain of Arg78. Sequence alignment of the two analogues with several species of MBP suggests a critical role for the positively charged residue Arg78, firstly, in the stabilization of the local microdomains (epitopes) of the integral protein, and secondly, in a number of post-translational modifications relevant to multiple sclerosis, such as the conversion of charged arginine residues to uncharged citrullines. Flexible docking calculations on the binding of the MBP(74-85) antigen to the MHC class II receptor site I-Au using HADDOCK indicate that Gln74, Ser76 and Ser79 are MHC II anchor residues. Lys75, Arg78 and Asp81 are prominent, solvent-exposed residues and, thus, may be of importance in the formation of the trimolecular T-cell receptor-MBP(74-85)-MHC II complex.
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Keywords: Conformation, Docking, Major histocompatibility complex, Molecular dynamics, Myelin basic epitope, dimethyl sulfoxide, epitope, major histocompatibility antigen class 2, myelin basic protein[74-85], myelin basic protein[74-85][81 alanine], peptide derivative, protein inhibitor, unclassified drug, water, allergic encephalomyelitis, amino acid substitution, antigen binding, article, binding affinity, binding site, calculation, complex formation, conformational transition, major histocompatibility complex, molecular dynamics, multiple sclerosis, nuclear magnetic resonance, peptide analysis, priority journal, protein binding, protein conformation, protein modification, protein protein interaction, sequence alignment, structure activity relation, Taverne
ISSN: 0014-2956
Publisher: Academic Press Inc.
(Peer reviewed)