Department of Medicine, Duke University School of Medicine, Durham, NC, 27710, USA.
College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
Nat Commun. 2019 Feb 8;10(1):654. doi: 10.1038/s41467-019-08415-7.
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.
抗体可变区和框架区（FWR）内的体细胞突变会改变热稳定性和结构灵活性，但它们对功能效力的影响尚不清楚。在这里，我们研究了热稳定性，并使用分子动力学（MD）模拟来评估 FWR 突变在 HIV-1 广谱中和抗体（bnAb）成熟过程中的作用。经过测试的 bnAb 比其未突变的原始抗体具有更低的热稳定性。Fab 肘区的 FWR 突变在 HIV-1 bnAb 中经常观察到，MD 模拟表明，这种 FWR 突变会改变两种 HIV-1 bnAb 中的结构域间灵活性。在 CD4 结合位点谱系中，逆转突变导致对自体和异源 Tier-2 病毒的早期中间和亲和力成熟的 bnAb 的中和效力丧失，分别。糖基-V3 bnAb 中肘区的逆转突变会适度降低对自体病毒分离株的效力。因此，Fab 肘区突变的选择会影响 bnAb 发育过程中结构域间构象灵活性和表位可塑性。
