SARS-CoV-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity.
SARS-CoV-2 Delta Variant Decreases Nanobody Binding and ACE2 Blocking Effectivity.
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DOI：
10.1021/acs.jcim.1c01523
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发表时间：
2022-05-23
影响因子：
5.6
通讯作者：
Gur, Mert
中科院分区：
文献类型：
--
作者：
Golcuk, Mert;Hacisuleyman, Aysima;Yilmaz, Sema Zeynep;Taka, Elhan;Yildiz, Ahmet;Gur, Mert
Delta变异体比SARS-CoV-2以前的变异体传播得更快。该变体在其刺突糖蛋白的受体结合结构域（RBDDelta）上包含几个突变，所述刺突糖蛋白结合宿主细胞中的血管紧张素转化酶2（ACE 2）受体的肽酶结构域（PD）。RBD-PD相互作用已被抗体和纳米抗体靶向以预防病毒感染，但它们对Delta变体的有效性仍不清楚。在这里，我们通过进行21.8 μs的全原子分子动力学模拟，研究了在存在和不存在纳米抗体H11-H4、H11-D4和Ty 1的情况下RBDDelta-PD相互作用。无偏模拟显示，Delta变体突变通过增加疏水相互作用和盐桥形成来加强RBD与ACE 2的结合，但削弱与H11-H4、H11-D4和Ty 1的相互作用。在这些纳米抗体中，H11-H4和H11-D4结合RBD而不重叠ACE 2。当与RBD上的ACE 2并排结合时，它们不能使ACE 2从RBD Delta上脱位。在与高速原子力显微镜（AFM）实验相当的加载速率下，转向分子动力学模拟估计与ACE 2相比，RBDDelta的纳米抗体的断裂力较低。我们的研究结果表明，现有的纳米抗体抑制RBDDelta-PD相互作用的效果较差，需要新一代的纳米抗体来中和Delta变体。
The Delta variant spreads more rapidly than previous variants of SARS-CoV-2. This variant comprises several mutations on the receptor-binding domain (RBDDelta) of its spike glycoprotein, which binds to the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors in host cells. The RBD–PD interaction has been targeted by antibodies and nanobodies to prevent viral infection, but their effectiveness against the Delta variant remains unclear. Here, we investigated RBDDelta–PD interactions in the presence and absence of nanobodies H11-H4, H11-D4, and Ty1 by performing 21.8 μs of all-atom molecular dynamics simulations. Unbiased simulations revealed that Delta variant mutations strengthen RBD binding to ACE2 by increasing the hydrophobic interactions and salt bridge formation, but weaken interactions with H11-H4, H11-D4, and Ty1. Among these nanobodies H11-H4 and H11-D4 bind RBD without overlapping ACE2. They were unable to dislocate ACE2 from RBDDelta when bound side by side with ACE2 on RBD. Steered molecular dynamics simulations at comparable loading rates to high-speed atomic force microscopy (AFM) experiments estimated lower rupture forces of the nanobodies from RBDDelta compared to ACE2. Our results suggest that existing nanobodies are less effective to inhibit RBDDelta–PD interactions and a new generation of nanobodies is needed to neutralize the Delta variant.
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超越屏蔽：聚糖在SARS-COV-2尖峰蛋白中的作用。
影响因子：
18.2
作者：
Casalino L;Gaieb Z;Goldsmith JA;Hjorth CK;Dommer AC;Harbison AM;Fogarty CA;Barros EP;Taylor BC;McLellan JS;Fadda E;Amaro RE
通讯作者：
Amaro RE
影响因子：
12.4
作者：
Chakravarty R;Goel S;Cai W
通讯作者：
Cai W
影响因子：
3.4
作者：
Cao W;Dong C;Kim S;Hou D;Tai W;Du L;Im W;Zhang XF
通讯作者：
Zhang XF
影响因子：
16.8
作者：
Huo, Jiangdong;Le Bas, Audrey;Naismith, James H.
通讯作者：
Naismith, James H.
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.