Molecular modeling of hen egg lysozyme HEL[52-61] peptide binding to I-A(k) MHC class II molecule

A bound conformation of the antigenic decapeptide hen egg lysozyme HEL[52-6 1] associated to the mouse MHC class II (MHC II) I-A(k) was modeled by homo logy with the three-dimensional structure of hemagglutinin HA[306-318]-HLA- DR1 complex, HEL peptide Tyr53 could not be aligned with the HA peptide Tyr 308 because this resulted in a buried Tyr53 side chain within the I-A(k) pe ptide-binding groove and this conflicted with this side chain being recogni zed by T cells. Therefore, Asp52 of HEL was fixed as the P1 anchor and alig ned on Tyr308 of HA, After molecular dynamics, the modeled complex was stab le even in the absence of any constraint. The peptide backbone adopted a po lyproline II-like conformation with canonical hydrogen bonding between the peptide backbone and MHC II molecule, Asp52, Ile55, Gln57 and Ser60 were pr edicted to be deeply buried into P1, P4, P6 and is MHC II pockets, and Tyr5 3, Leu56, Asn59 and Arg61 as TCR contacting residues. The modeling of 15 co mplexes associating I-A(k) with peptides derived from HEL[52-61] by single amino acid substitution proved stable with conserved hydrogen bonds and sid e chain orientation compatible with their recognition by two T cell hybrido mas, Moreover, comparison with the recently solved crystal structure of the related HEL[50-62]-I-A(k) complex revealed striking similarities.