title: The complex and specific pMHC interactions with diverse HIV-1 TCR clonotypes reveal a structural basis for alterations in CTL function.
abstract: 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.
authors: 1] Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA [2].
authors: Zhen
authors: Z
authors: Xia
authors: 1] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA [2].
authors: Huabiao
authors: H
authors: Chen
authors: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA.
authors: Seung-gu
authors: SG
authors: Kang
authors: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA.
authors: Tien
authors: T
authors: Huynh
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
authors: Justin W
authors: JW
authors: Fang
authors: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA.
authors: Pedro A
authors: PA
authors: Lamothe
authors: 1] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA [2] Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Bruce D
authors: BD
authors: Walker
authors: 1] Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA [2] Department of Chemistry, Columbia University, New York, New York, USA.
authors: Ruhong
authors: R
authors: Zhou
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D000939:Epitopes / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015497:HIV-1 / Q000378:metabolism*; D015796:HLA-B27 Antigen / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D016296:Mutagenesis; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000939:Epitopes; C464936:HLA-B*27:05 antigen; D015796:HLA-B27 Antigen; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011948:Receptors, Antigen, T-Cell