title: A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis.
abstract: Myelin basic protein (MBP) is one of the best characterized autoantigens causing multiple sclerosis (MS), via a procedure that involves a stable formation of the trimolecular complex of a T-cell Receptor (TCR), an MBP epitope, and the receptor HLA-DR2b. Experimental autoimmune encephalomyelitis (EAE) is considered as an instructive model for MS in humans, and plenty of X-ray data is available for a number of EAE inducing peptide-receptor complexes. To date, though, there are no data available for complexes involving peptides reversing EAE, namely antagonists. Conformational properties of the EAE inducing epitope MBP(87-99) were analyzed in DMSO using the NOE connectivities and vicinal H(N)-H(alpha) coupling constants, and compared with the antagonist altered peptide ligands. A robust method, which is based on a combination of molecular dynamics and energy minimization, is proposed for identifying the putative bioactive conformations. Generated conformations are compared with the known X-ray structure of MBP(83-96) (human sequence numbering) in the HLA-DR2b complex. The structural motif for the agonist-antagonist activity is discussed.
authors.affiliation: Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Avenue, 116 35, Athens, Greece; Department of Chemistry, University of Patras, 265 00, Rion, Patras, Greece.
authors.forename: Efthimia D
authors.initials: ED
authors.lastname: Mantzourani
authors.forename: Klemen
authors.initials: K
authors.lastname: Blokar
authors.forename: Theodore V
authors.initials: TV
authors.lastname: Tselios
authors.forename: John M
authors.initials: JM
authors.lastname: Matsoukas
authors.forename: James A
authors.initials: JA
authors.lastname: Platts
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Mavromoustakos
authors.forename: Simona Golic
authors.initials: SG
authors.lastname: Grdadolnik
mesh_terms: D000469:Alkaline Phosphatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D003198:Computer Simulation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011522:Protons; D013696:Temperature
chemical_list: D000577:Amides; D004676:Myelin Basic Protein; D011522:Protons; D000469:Alkaline Phosphatase