Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor
Critical Interactions Between the SARS-CoV-2 Spike Glycoprotein and the Human ACE2 Receptor
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DOI：
10.1021/acs.jpcb.1c02048
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发表时间：
2021-05-12
影响因子：
3.3
通讯作者：
Gur, Mert
中科院分区：
文献类型：
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作者：
Taka, Elhan;Yilmaz, Sema Z.;Gur, Mert
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）通过将其刺突（S）糖蛋白与血管紧张素转换酶2（ACE 2）受体结合感染人类细胞，并导致2019冠状病毒病（COVID-19）。预防SARS-CoV-2感染的治疗方法主要集中在阻断S-ACE 2结合，但稳定这种相互作用的关键残基尚未得到很好的理解。通过进行全原子分子动力学（MD）模拟，我们确定了一个扩展的网络的盐桥，疏水和静电相互作用，和S蛋白和ACE 2的受体结合域（RBD）之间的氢键。RBD上这些残基的突变不足以使结合不稳定，但减少了使S蛋白与ACE 2解结合的平均工作。特别地，RBD的疏水末端充当主要锚位点，并且是在力的作用下最后从ACE 2解结合的位点。我们提出，通过中和抗体阻断RBD的疏水表面可能被证明是抑制S-ACE 2相互作用的有效策略。
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects human cells by binding its spike (S) glycoproteins to angiotensin-converting enzyme 2 (ACE2) receptors and causes the coronavirus disease 2019 (COVID-19). Therapeutic approaches to prevent SARS-CoV-2 infection are mostly focused on blocking S-ACE2 binding, but critical residues that stabilize this interaction are not well understood. By performing all-atom molecular dynamics (MD) simulations, we identified an extended network of salt bridges, hydrophobic and electrostatic interactions, and hydrogen bonds between the receptor-binding domain (RBD) of the S protein and ACE2. Mutagenesis of these residues on the RBD was not sufficient to destabilize binding but reduced the average work to unbind the S protein from ACE2. In particular, the hydrophobic end of RBD serves as the main anchor site and is the last to unbind from ACE2 under force. We propose that blocking the hydrophobic surface of RBD via neutralizing antibodies could prove to be an effective strategy to inhibit S-ACE2 interactions.