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

Abstract

The two new synthetic analogues of the MBP(83-99) epitope substituted at Lys(91) (primary TCR contact) 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 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 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 conformational characteristics of the MBP(83-99) 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.

Engineering chimeric autoantibody receptor T cells for targeted B cell depletion in multiple sclerosis model: An in-vitro study

“…However, the 80–105 amino acid residues are among the most commonly recognized sites [ 30 ]. In fact, the immunodominant epitope of MBP is the 83–99 amino-acid residues, which showed the strongest binding affinity to the HLA-DR2 haplotype [ 31 , 32 ].…”

Myelin-derived and putative molecular mimic peptides share structural properties in aqueous and membrane-like environments

“…The y axis contains the relative signal at 195 nm the helical conformation, and they point outward from the MHC complex; these are the positions that MHC presents to the T cell. Mutation of these positions in the MBP85-99 epitope lead to altered immunological response [52,53].…”

Mannosylated Linear and Cyclic Single Amino Acid Mutant Peptides Using a Small 10 Amino Acid Linker Constitute Promising Candidates Against Multiple Sclerosis

“…Although T cells from healthy individuals also recognize MBP 83–99 the precursor frequencies are relatively low. The binding of MBP 83–99 to HLA-DR2 is via hydrophobic V 87 and F 90 residues, and, V 86 , H 88 , F 89 , and K 91 being TCR contact residues ( 10 – 15 ). Residue P 96 is also a TCR contact site based on the crystal structure of HLA-DR2α-MBP 89–101 complex ( 16 ).…”