The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function

• Published in: Scientific reports 2014-02, Vol.4 (1), p.4087, Article 4087
• Main Authors: Xia, Zhen, Chen, Huabiao, Kang, Seung-gu, Huynh, Tien, Fang, Justin W., Lamothe, Pedro A., Walker, Bruce D., Zhou, Ruhong
• Format: Article
• Language: English
• Subjects: 119/118; 13/21; 13/51; 45/70; 631/114/2397; 631/114/2410; 631/250/255/1901; 631/57/2272/2274; Binding Sites; Crystal structure; Crystallography, X-Ray; Cytotoxicity; Epitopes; Epitopes - genetics; Epitopes - immunology; Epitopes - metabolism; Free energy; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; HIV-1 - metabolism; HLA-B27 Antigen - chemistry; HLA-B27 Antigen - genetics; HLA-B27 Antigen - metabolism; Humanities and Social Sciences; Hydrogen Bonding; Hydrophobicity; Lymphocytes T; Major histocompatibility complex; Models, Molecular; Molecular Dynamics Simulation; Molecular modelling; multidisciplinary; Mutagenesis; Peptides; Peptides - genetics; Peptides - immunology; Peptides - metabolism; Protein Binding; Protein Structure, Quaternary; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - metabolism; Science; Structure-function relationships; T cell receptors; Thermodynamics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep04087

Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-MHC class I complexes on infected cells, but the relationship between TCR structure and antiviral function is unclear. Here we apply in silico molecular modeling with in vivo mutagenesis studies to investigate TCR-pMHC interactions from multiple CTL clonotypes specific for a well-defined HIV-1 epitope. Our molecular dynamics simulations of viral peptide-HLA-TCR complexes, based on two independent co-crystal structure templates, reveal that effective and ineffective clonotypes bind to the terminal portions of the peptide-MHC through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Furthermore, free energy perturbation calculations for point mutations on the viral peptide KK10 show excellent agreement with in vivo mutagenesis assays, with new predictions confirmed by additional experiments. These findings indicate a direct structural basis for heterogeneous CTL antiviral function.