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

The specific recognition of foreign peptide bound to the major histocompati bility complex (MHC) molecule by T-cell receptor (TCR) leads to T-cell acti vation. We found that analogue peptides containing single amino acid substi tutions at the third amino acid position (p3), p5, p7 and p8 of the index p eptide (YWALEAAAD) induced different response patterns of T cell clones spe cific for the index peptide in the context of the human MHC class II molecu le HLA-DR4. Analogue peptides were classified into three types, agonists, a ntagonists or null peptides (non-agonistic and non-antagonistic peptides), A molecular basis for how these slight changes lead to such different conse quences for T cells has not been described. To explore the mechanistic basi s 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-a ntagonist complexes. The simulations showed that the DR4-antagonist complex es were distinguished from the DR4-index peptide and DR4-agonist complexes by relatively higher deviations of C-alpha atoms in proposed TCR-binding re gions, suggesting that subtle changes of the exposed framework of the pepti de binding groove by the antagonist peptides could induce the TCR antagonis tic activities.