Conformational studies of immunodominant myelin basic protein 1–11 analogues using NMR and molecular modeling

Abstract

Τwo dimensional nuclear magnetic resonance studies complimented by molecular dynamics simulations were conducted to investigate the conformation of the immunodominant epitope of acetylated myelin basic protein residues 1-11 (Ac-MBP(1-11)) and its altered peptide ligands, mutated at position 4 to an alanine (Ac-MBP(1-11)[4A]) or a tyrosine residue (Ac-MBP(1-11)[4Y]). Conformational analysis of the three analogues indicated that they adopt an extended conformation in DMSO solution as no long distance NOE connectivities were observed and seem to have a similar conformation when bound to the active site of the major histocompatibility complex (MHC II). The interaction of each peptide with MHC class II I-A(u) was further investigated in order to explore the molecular mechanism of experimental autoimmune encephalomyelitis induction/inhibition in mice. The present findings indicate that the Gln(3) residue, which serves as a T-cell receptor (TCR) contact site in the TCR/peptide/I-A(u) complex, has a different orientation in the mutated analogues especially in the Ac-MBP(1-11)[4A] peptide. In particular the side chain of Gln(3) is not solvent exposed as for the native Ac-MBP(1-11) and it is not available for interaction with the TCR.

Large Scale Characterization of the LC13 TCR and HLA-B8 Structural Landscape in Reaction to 172 Altered Peptide Ligands: A Molecular Dynamics Simulation Study

“…This closeness is often reflected in the solvent accessible surface area of interface components. For example Stavrakoudis et al [37] reported an increased solvation of the LC13/FLRGRAYGL/HLA-B*08:01 interface, Madura et al observed solvation as important for peptide specificity [68], and Laimou et al [23] found that 3G of the immunodominant myelin basic protein (MBP) peptide presented by I-Au is more solvent exposed as the analogues 4A and 4Y.…”

Unraveling the Allosteric Communication Mechanisms in T-Cell Receptor–Peptide-Loaded Major Histocompatibility Complex Dynamics Using Molecular Dynamics Simulations: An Approach Based on Dynamic Cross Correlation Maps and Residue Interaction Energy Calculations

“…Although the cryo-EM structure revealed much about the role of TM helices of CD3 in complex integrity, the chemical cross-linking may prevent the TCR–CD3 to explore different conformations; hence, the dynamic studies on the complex system would be better suited for examining the allosteric effect on TCRs . To this end, molecular dynamics (MD) simulations were previously employed to investigate TCR–pMHC dynamics, focusing on the effects of different peptides, the interaction between the peptide and MHC, − TCR–MHC interaction sites, ,− different TCR , or MHC molecules, − and binding groove properties of MHC molecules. − …”

A Journey to the Conformational Analysis of T-Cell Epitope Peptides Involved in Multiple Sclerosis

“…Specifically, its side chain is not solvent exposed, and it is not available for interaction with the TCR. The main MHC contact residues (Ser 2 , Pro 6 and Ser 7 ) stand in the same position for all peptides [54].…”