title: Magnitude of structural changes of the T-cell receptor binding regions determine the strength of T-cell antagonism: molecular dynamics simulations of HLA-DR4 (DRB1*0405) complexed with analogue peptide.
abstract: In our model system, we generated T cell clones specific for the HLA-DR4 (DRB1*0405)-index peptide (YWALEAAAD) complex. Based on response patterns of the T cell clones, analogue peptides containing single amino acid substitutions of the index peptide were classified into three types, agonists, antagonists or null peptides (non-agonistic and non-antagonistic peptides). Subtle structural changes induced by the antagonists in the T-cell receptor (TCR) binding regions have already been explained using the root mean square (r.m.s.) deviations from the DR4-index peptide complex in the molecular dynamics (MD) trajectory. In this work, we performed additional MD simulations at 300 K with explicit solvent molecules to reveal the structural character of the HLA-DR4 complexed with the analogue peptides. We examined the r.m.s. deviations of the TCR-binding sites and the exposed areas of the bound peptides. Remarkable differences of the r.m.s. deviations among the DR4-antagonist complexes, together with our previous data, suggest that the magnitude of structural changes of TCR-binding regions would determine the strength of TCR antagonism. The simulations also indicate that TCR could discriminate null peptides from other ligands mainly through the changes of exposed side chains of the bound peptide, rather than the conformational changes of TCR-binding surfaces on HLA molecule.
authors.affiliation: Graduate School of Genetic Resources Technology, Kyushu University, Hakozaki, Higashi-ku, Fukuoka 812-8581, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Toh
authors.forename: N
authors.initials: N
authors.lastname: Kamikawaji
authors.forename: T
authors.initials: T
authors.lastname: Tana
authors.forename: S
authors.initials: S
authors.lastname: Muta
authors.forename: T
authors.initials: T
authors.lastname: Sasazuki
authors.forename: S
authors.initials: S
authors.lastname: Kuhara
mesh_terms: D001665:Binding Sites / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D003198:Computer Simulation; D006684:HLA-DR Antigens / Q000737:chemistry*; D015804:HLA-DR4 Antigen / Q000737:chemistry*; D059811:HLA-DRB1 Chains; D006801:Humans; D008024:Ligands; D008954:Models, Biological; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006684:HLA-DR Antigens; D015804:HLA-DR4 Antigen; D059811:HLA-DRB1 Chains; D008024:Ligands; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell