Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35-55 epitope implicated in multiple sclerosis.

Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction.

A combined NMR and molecular dynamics simulation study to determine the conformational properties of agonists and antagonists against experimental autoimmune encephalomyelitis.

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.

Putative bioactive conformations of amide linked cyclic myelin basic protein peptide analogues associated with experimental autoimmune encephalomyelitis.

The solution models of cyclo(87-99) MBP87-99, cyclo(87-99) [Ala91,96] MBP87-99, and cyclo(87-99) [Arg91, Ala96] MBP87-99 have been determined through 2D NMR spectroscopy in DMSO-d6. Chemical shift analysis has been performed in an attempt to elucidate structural changes occurring upon substitution of native residues. NMR-derived geometrical constraints have been used in order to calculate high-resolution conformers of the above peptides.

Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87-99 implicated in multiple sclerosis and its antagonists altered peptide ligands: triggering of immune response.

This work reports molecular dynamics studies at the receptor level of the immunodominant myelin basic protein (MBP) epitope 87-99 implicated in multiple sclerosis, and its antagonists altered peptide ligands (APLs), namely [Arg91, Ala96] MBP87-99 and [Ala91,96] MBP87-99. The interaction of each peptide ligand with the receptor human leukocyte antigen HLA-DR2b was studied, starting from X-ray structure with pdb code: 1ymm. This is the first such study of APL-HLA-DR2b complexes, and hence the first attempt to gain a better understanding of the molecular recognition mechanisms that underlie TCR antagonism by these APLs.

Comparison of proposed putative active conformations of myelin basic protein epitope 87-99 linear altered peptide ligands by spectroscopic and modelling studies: the role of positions 91 and 96 in T-cell receptor activation.

This work proposes a structural motif for the inhibition of experimental autoimmune encephalomyelitis (EAE) by the linear altered peptide ligands (APLs) [Ala91,96] MBP87-99 and [Arg91,Ala96] MBP87-99 of myelin basic protein. Molecular dynamics was applied to reveal distinct populations of EAE antagonist [Ala91,96] MBP87-99 in solution, in agreement with NOE data. The combination of the theoretical and experimental results led to the identification of a putative active conformation.

Design, synthesis, and molecular modeling of a novel amide-linked cyclic GnRH analogue cyclo(4-9)[Lys4,D-Trp6,Glu9]GnRH: stimulation of gonadotropin gene expression.

This report describes the rational design, synthesis, and pharmacological properties of an amide-linked cyclic analogue of gonadotropin-releasing hormone (GnRH) namely Cyclo(4-9)[Lys(4),d-Trp(6),Glu(9)]GnRH. The conformationally restricted analogue is characterized by reduced flexibility of the peptide strand due to the introduction of a beta-turn mimetic through 4,9 residue amide cyclization. The cyclic analogue was found to stimulate gonadotropin gene expression in the goldfish pituitary with similar potency compared to two native forms of GnRH.

Design and synthesis of a novel potent myelin basic protein epitope 87-99 cyclic analogue: enhanced stability and biological properties of mimics render them a potentially new class of immunomodulators.

A cyclic analogue, [cyclo(87-99)MBP(87)(-)(99)], of the human immunodominant MBP(87)(-)(99) epitope, was designed based on ROESY/NMR distance information and modeling data for linear epitope 87-99, taking into account T-cell (Phe(89), Lys(91), Pro(96)) and HLA (His(88), Phe(90), Ile(93)) contact side-chain information. The cyclic analogue was found to induce experimental allergic encephalomyelitis (EAE), to bind HLA-DR4, and to increase CD4 T-cell line proliferation, like that of the conformationally related linear MBP(87)(-)(99) epitope peptide. The mutant cyclic peptides, the cyclo(91-99)[Ala(96)]MBP(87)(-)(99) and the cyclo(87-99)[Arg(91)Ala(96)]MBP(87)(-)(99), reported previously for suppressing, to a varying degree, autoimmune encephalomyelitis in a rat animal model, were found in this study to possess the following immunomodulatory properties: (i) they suppressed the proliferation of a CD4 T-cell line raised from a multiple sclerosis patient, (ii) they scored the best in vitro TH2/TH1 cytokine ratio in peripheral blood mononuclear cell cultures derived from 13 multiple sclerosis patients, inducing IL-10 selectively, and (iii) they bound to HLA-DR4, first to be reported for cyclic MBP peptides.