Molecular dynamics simulations of HLA-DR4 (DRB1*0405) complexed with analogue peptide: Conformational changes in the putative T-cell receptor binding regions

The specific recognition of foreign peptide bound to the major histocompatibility complex (MHC) molecule by T-cell receptor (TCR) leads to T-cell activation. We found that analogue peptides containing single amino acid substitutions at the third amino acid position (p3), p5, p7 and p8 of the index peptide (YWALEAAAD) induced different response patterns of T cell clones specific for the index peptide in the context of the human MHC class II molecule HLA-DR4. Analogue peptides were classified into three types, agonists, antagonists or null peptides (non-agonistic and non-antagonistic peptides). A molecular basis for how these slight changes lead to such different consequences for T cells has not been described. To explore the mechanistic basis of these observations, molecular dynamics simulations at 300 K of 300 ps duration were carried out for the DR4-index peptide, DR4-agonist, and DR4-antagonist complexes. The simulations showed that the DR4-antagonist complexes were distinguished from the DR4-index peptide and DR4-agonist complexes by relatively higher deviations of C(α) atoms in proposed TCR-binding regions, suggesting that subtle changes of the exposed framework of the peptide binding groove by the antagonist peptides could induce the TCR antagonistic activities.