Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites
Enhanced Binding of SARS-CoV-2 Spike Protein to Receptor by Distal Polybasic Cleavage Sites
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DOI：
10.1021/acsnano.0c04798
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发表时间：
2020-08-25
期刊：
影响因子：
17.1
通讯作者：
de la Cruz, Monica Olvera
中科院分区：
文献类型：
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作者：
Qiao, Baofu;de la Cruz, Monica Olvera
SARS-CoV-2刺突蛋白的受体结合结构域（RBD）在结合病毒进入所需的人类细胞受体ACE 2方面起着至关重要的作用。已经进行了许多研究以靶向RBD-ACE 2结合的结构并设计靶向RBD的疫苗和药物。然而，SARS-CoV-2 RBD远端的突变也影响其传播性，抗体可以靶向非RBD区域，表明RBD区域在刺突蛋白-ACE 2结合中的作用不完全。在这里，为了阐明遥远的结合机制，我们分析复合物的ACE 2与野生型刺突蛋白和关键突变体通过大规模的全原子显式溶剂分子动力学模拟。我们发现，尽管分布在距离RBD约10 nm处，但SARS-CoV-2多碱切割位点通过静电相互作用和水合作用增强了RBD-ACE 2结合亲和力。然后设计带负电荷的四肽（GluGluLeuGlu）以中和多碱基切割位点上的带正电荷的精氨酸。我们发现四肽GluGluLeuGlu结合到SARS-CoV-2刺突蛋白的三个多碱基切割位点之一，使RBD-ACE 2结合强度降低34%。这种显著的结合能降低证明了通过靶向该特异性多元切割位点来中和RBD-ACE 2结合的可行性。我们的工作增强了对SARS-CoV-2与ACE 2结合机制的理解，这可能有助于设计COVID-19感染的治疗方法。
The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein plays a crucial role in binding the human cell receptor ACE2 that is required for viral entry. Many studies have been conducted to target the structures of RBD-ACE2 binding and to design RBD-targeting vaccines and drugs. Nevertheless, mutations distal from the SARS-CoV-2 RBD also impact its transmissibility and antibody can target non-RBD regions, suggesting the incomplete role of the RBD region in the spike protein-ACE2 binding. Here, in order to elucidate distant binding mechanisms, we analyze complexes of ACE2 with the wild-type spike protein and with key mutants via large-scale all-atom explicit solvent molecular dynamics simulations. We find that though distributed approximately 10 nm away from the RBD, the SARS-CoV-2 polybasic cleavage sites enhance, via electrostatic interactions and hydration, the RBD-ACE2 binding affinity. A negatively charged tetrapeptide (GluGluLeuGlu) is then designed to neutralize the positively charged arginine on the polybasic cleavage sites. We find that the tetrapeptide GluGluLeuGlu binds to one of the three polybasic cleavage sites of the SARS-CoV-2 spike protein lessening by 34% the RBD-ACE2 binding strength. This significant binding energy reduction demonstrates the feasibility to neutralize RBD-ACE2 binding by targeting this specific polybasic cleavage site. Our work enhances understanding of the binding mechanism of SARS-CoV-2 to ACE2, which may aid the design of therapeutics for COVID-19 infection.