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Binding Mechanism of Neutralizing Nanobodies Targeting SARS-CoV-2 Spike Glycoprotein
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2021-09-28 , DOI: 10.1021/acs.jcim.1c00695
Mert Golcuk 1 , Aysima Hacisuleyman 2 , Burak Erman 3 , Ahmet Yildiz 4, 5 , Mert Gur 1
Affiliation  

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.

中文翻译:

靶向 SARS-CoV-2 刺突糖蛋白的中和纳米抗体的结合机制

严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 在其刺突 (S) 糖蛋白与 ACE2 受体结合后进入人体细胞。几种纳米抗体通过与 S 蛋白的受体结合域 (RBD) 结合来中和 SARS-CoV-2 感染,但它们的结合如何拮抗 S-ACE2 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 Ty1 之间的相互作用。H11-H4 和 H11-D4 可以与 RBD 结合,而不与 ACE2 重叠。H11-H4 以及较小程度的 H11-D4,由于静电排斥,结合使 ACE2 从其结合位点移位。相比之下,Ty1 与 RBD 上的 ACE2 重叠,并且与 ACE2 具有相似的结合强度。SARS-CoV-2 的 Alpha 变体的突变对 ACE2 和纳米抗体的 RBD 结合强度影响较小,但降低了 H11-H4 和 H11-D4 将 ACE2 从 RBD 上脱位的能力。相比之下,Beta 变体削弱了 H11-H4 和 H11-D4 的 RBD 结合强度,这对于使 ACE2 结合错位的效果较差。出乎意料的是,Beta 的突变增强了 Ty1 与 RBD 的结合,表明这种纳米抗体可能更有效地中和 SARS-CoV-2 的 Beta 变体。
更新日期:2021-10-25
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