Molecular modeling of hen egg lysozyme HEL[52-61] peptide binding to I-Ak MHC class II molecule.

Abstract

A bound conformation of the antigenic decapeptide hen egg lysozyme HEL[52-61] associated to the mouse MHC class II (MHC II) I-Ak was modeled by homology with the three-dimensional structure of hemagglutinin HA[306-318]-HLA-DR1 complex. HEL peptide Tyr53 could not be aligned with the HA peptide Tyr308 because this resulted in a buried Tyr53 side chain within the I-Ak peptide-binding groove and this conflicted with this side chain being recognized by T cells. Therefore, Asp52 of HEL was fixed as the P1 anchor and aligned on Tyr308 of HA. After molecular dynamics, the modeled complex was stable even in the absence of any constraint. The peptide backbone adopted a polyproline II-like conformation with canonical hydrogen bonding between the peptide backbone and MHC II molecule. Asp52, IIe55, Gin57 and Ser60 were predicted to be deeply buried into P1, P4, P6 and P9 MHC II pockets, and Tyr53, Leu56, Asn59 and Arg61 as TCR contacting residues. The modeling of 15 complexes associating I-Ak with peptides derived from HEL[52-61] by single amino acid substitution proved stable with conserved hydrogen bonds and side chain orientation compatible with their recognition by two T cell hybridomas. Moreover, comparison with the recently solved crystal structure of the related HEL[50-62]-I-Ak complex revealed striking similarities.

(E)-Alkene and Ethylene Isosteres Substantially Alter the Hydrogen-Bonding Network in Class II MHC Aq/Glycopeptide Complexes and Affect T-Cell Recognition

“…5,7À9 For example, the exposed peptide surface area derived from MD data for a series of class II MHC-bound substituted hen egg lysozyme (HEL) peptides was correlated with their T-cell responses. 5 Furthermore, conformational changes in the MHC binding of different peptides observed in MD simulations have been linked to T-cell responsiveness and experimental autoimmune encephalomyelitis (EAE) induction in vivo. 7 We have recently linked flexibility and changes in the presented epitope of MHC anchor-modified glycopeptides to different T-cell responses.…”

Changes at the floor of the peptide-binding groove induce a strong preference for Proline at position 3 of the bound peptide: Molecular dynamics simulations of HLA-A*0217

“…These results indicate that the interaction of the p6 side chain with A*0217 would contribute to the tight binding of the peptides (Figure 4C). Hydrogen bonding between MHC molecule and the bound peptide is thought to be one of the major binding forces 39. In A*0201 complexes, Arg97 and Tyr99 side chains form hydrogen bonds to the bound peptide (data not shown).…”

Peptide Chemistry's Contribution to the Treatment of the Majority of Serious Illnesses: Peptide Antitumors.

“…In order to probe immunogenic conformation of this peptide we have used amino acids which constrain the space available to the Tyr 53 side chain. The results show that the side chain conformation, play a significant role in the recognition of the peptide by the T-cells [127][128][129].…”