Xia Zhen, Chen Huabiao, Kang Seung-gu, Huynh Tien, Fang Justin W, Lamothe Pedro A, Walker Bruce D, Zhou Ruhong
1] Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York, USA [2].
1] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, Massachusetts, USA [2].
Sci Rep. 2014 Feb 13;4:4087. 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.
病毒感染的免疫控制由与受感染细胞上的肽 - 主要组织相容性复合体I类（pMHC）结合的多种T细胞受体（TCR）克隆型调节，但TCR结构与抗病毒功能之间的关系尚不清楚。在这里，我们应用计算机模拟分子建模和体内诱变研究，以研究针对明确的HIV - 1表位的多种CTL克隆型的TCR - pMHC相互作用。我们基于两个独立的共晶体结构模板对病毒肽 - HLA - TCR复合物进行的分子动力学模拟表明，有效和无效的克隆型通过相似的盐桥与肽 - MHC的末端部分结合，但其疏水侧链堆积可能非常不同，这是这些克隆型之间差异的主要部分。与病毒肽的非特异性氢键也能容纳更多的表位变体。此外，对病毒肽KK10上点突变的自由能扰动计算与体内诱变试验显示出极好的一致性，新的预测通过额外的实验得到证实。这些发现表明了CTL抗病毒功能异质性的直接结构基础。
