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

Hidehiro Toh, Nobuhiro Kamikawaji, Takeshi Tana, Shigeru Muta, Takehiko Sasazuki, Satoru Kuhara

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

In our model system, we generated T cell clones specific for the HLA-DR4 (DRB1*0405)-index peptide (YWA-LEAAAD) 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.

Original languageEnglish
Pages (from-to)423-429
Number of pages7
JournalProtein Engineering
Volume13
Issue number6
Publication statusPublished - Jul 24 2000

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HLA-DR4 Antigen
T-cells
Molecular Dynamics Simulation
T-Cell Antigen Receptor
Peptides
Molecular dynamics
T-Lymphocytes
Computer simulation
Clone Cells
HLA-DRB1*04:05 antigen
Molecules
Binding sites
Amino Acid Substitution
Amino acids
Substitution reactions
Binding Sites
Ligands
Trajectories

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology

Cite this

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. / Toh, Hidehiro; Kamikawaji, Nobuhiro; Tana, Takeshi; Muta, Shigeru; Sasazuki, Takehiko; Kuhara, Satoru.

In: Protein Engineering, Vol. 13, No. 6, 24.07.2000, p. 423-429.

Research output: Contribution to journalArticle

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