Selection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies
Selection of immunoglobulin elbow region mutations impacts interdomain conformational flexibility in HIV-1 broadly neutralizing antibodies
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DOI：
10.1038/s41467-019-08415-7
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发表时间：
2019-02-08
影响因子：
16.6
通讯作者：
Alam, S. Munir
中科院分区：
文献类型：
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作者：
Henderson, Rory;Watts, Brian E.;Alam, S. Munir
抗体可变区和框架区（FWR）内的体细胞突变可以改变热稳定性和结构灵活性，但其对功能效力的影响尚不清楚。在这里，我们研究热稳定性，并使用分子动力学（MD）模拟，以评估FWR突变在HIV-1广泛中和抗体（bnAb）成熟过程中的作用。测试的bnAb显示出比其未突变的祖先抗体更低的热稳定性。在HIV-1 bnAb中经常观察到Fab肘区的FWR突变，MD模拟表明，这种FWR突变改变了两种HIV-1 bnAb中的结构域间柔性。在CD 4结合位点谱系中，回复突变导致早期中间体和亲和力成熟bnAb分别针对自体和异源Tier-2病毒的中和效力丧失。聚糖-V3 bnAb中的肘部区域回复突变适度降低了针对自体病毒分离株的效力。因此，Fab肘区突变的选择影响bnAb开发过程中的结构域间构象灵活性和互补位可塑性。
Somatic mutations within antibody variable and framework regions (FWR) can alter thermostability and structural flexibility, but their impact on functional potency is unclear. Here we study thermostability and use molecular dynamics (MD) simulations to assess the role of FWR mutations during maturation of HIV-1 broadly neutralizing antibodies (bnAbs). The tested bnAbs show lower thermostability than their unmutated ancestor antibodies. FWR mutations in the Fab elbow region are frequently observed in HIV-1 bnAbs and MD simulations show that such FWR mutations alter interdomain flexibility in two HIV-1 bnAbs. In a CD4-binding site lineage, reversion mutations result in a loss of neutralization potency in an early intermediate and affinity-matured bnAb against autologous and heterologous Tier-2 viruses, respectively. Elbow region reversion mutations in a glycan-V3 bnAb modestly reduces potency against an autologous virus isolate. Thus, selection of mutations in the Fab elbow region impacts interdomain conformational flexibility and paratope plasticity during bnAb development.