Binding Mechanism of Neutralizing Nanobodies Targeting SARS-CoV-2 Spike Glycoprotein
Binding Mechanism of Neutralizing Nanobodies Targeting SARS-CoV-2 Spike Glycoprotein
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DOI：
10.1021/acs.jcim.1c00695
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发表时间：
2021-09-28
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;Gur, Mert
严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）通过其刺突（S）糖蛋白与ACE 2受体结合进入人体细胞。几种纳米抗体通过与S蛋白的受体结合结构域（RBD）结合来中和SARS-CoV-2感染，但它们的结合如何拮抗S-ACE 2相互作用尚不清楚。在这里，我们通过进行全原子分子动力学模拟确定了RBD与纳米抗体H11-H4、H11-D4和Ty 1之间的相互作用。H11-H4和H11-D4可以与RBD结合而不与ACE 2重叠。H11-H4和较小程度的H11-D4的结合由于静电排斥而使ACE 2从其结合位点移位。相比之下，Ty 1在RBD上与ACE 2重叠，并且与ACE 2具有相似的结合强度。SARS-CoV-2的α变体中的突变对ACE 2和纳米抗体的RBD结合强度具有较小的影响，但降低了H11-H4和H11-D4从RBD移位ACE 2的能力。相比之下，β变体减弱了H11-H4和H11-D4的RBD结合强度，这对移位ACE 2结合不太有效。出乎意料的是，β突变增强了Ty 1与RBD的结合，这表明这种纳米抗体可能更有效地中和SARS-CoV-2的β变体。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters human cells upon binding of its spike (S) glycoproteins to ACE2 receptors. Several nanobodies neutralize SARS-CoV-2 infection by binding to the receptor-binding domain (RBD) of the S protein, but how their binding antagonizes S-ACE2 interactions is not well understood. Here, we identified interactions between the RBD and nanobodies H11-H4, H11-D4, and Ty1 by performing all-atom molecular dynamics simulations. H11-H4 and H11-D4 can bind to RBD without overlapping with ACE2. H11-H4, and to a lesser extent H11-D4, binding dislocates ACE2 from its binding site due to electrostatic repulsion. In comparison, Ty1 overlaps with ACE2 on RBD and has a similar binding strength to ACE2. Mutations in the Alpha variant of SARS-CoV-2 had a minor effect in RBD binding strengths of ACE2 and nanobodies, but reduced the ability of H11-H4 and H11-D4 to dislocate ACE2 from RBD. In comparison, the Beta variant weakened the RBD binding strengths of H11-H4 and H11-D4, which were less effective to dislocate ACE2 binding. Unexpectedly, mutations in Beta strengthened Ty1 binding to RBD, suggesting that this nanobody may be more effective to neutralize the Beta variant of SARS-CoV-2.