Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data
Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data
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DOI：
10.1002/jcp.30367
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发表时间：
2021-03-23
影响因子：
5.6
通讯作者：
Wei, Dong-Qing
中科院分区：
文献类型：
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作者：
Khan, Abbas;Zia, Tauqir;Wei, Dong-Qing
据报道，SARS-CoV-2新变种的传染性比之前的变种高70%，目前正在全球范围内迅速传播。现在迫切需要发现新的变异是如何与宿主受体（ACE2）相互作用的。在报道的新变异穗糖蛋白突变中，有三个是特异性的受体结合结构域（RBD），需要深入研究新的治疗方案。RBD结构域的这些结构进化可能对SARS-CoV-2新变体的独特致病性起关键作用。本文采用结构和生物物理方法，研究了英国（N501Y）、南非（K417N-E484K-N501Y）、巴西（K417T-E484K-N501Y）和假设（N501Y- e481y）变异的特异性突变改变了结合亲和力，创造了新的蛋白间接触，改变了内部结构动力学，从而增加了结合并最终提高了传染性。我们的调查强调南非（K417N-E484K-N501Y）、巴西（K417T-E484K-N501Y）变种比英国变种（N501Y）更致命。野生型和N501Y的行为具有可比性。自由能计算进一步证实了尖峰RBD与ACE2结合的增加主要是由于静电的贡献。此外，我们发现这种病毒的不同寻常的毒力可能是达尔文选择驱动的上位性在蛋白质进化中的结果。三突变体（南非和巴西）可能对已经开发的疫苗的效力构成严重威胁。我们的分析将有助于理解Spike蛋白RBD结构域新突变的结合和结构动力学，并需要在体外和体内模型中进一步研究，以设计针对新变体的潜在治疗方法。
The evolution of the SARS-CoV-2 new variants reported to be 70% more contagious than the earlier one is now spreading fast worldwide. There is an instant need to discover how the new variants interact with the host receptor (ACE2). Among the reported mutations in the Spike glycoprotein of the new variants, three are specific to the receptor-binding domain (RBD) and required insightful scrutiny for new therapeutic options. These structural evolutions in the RBD domain may impart a critical role to the unique pathogenicity of the SARS-CoV-2 new variants. Herein, using structural and biophysical approaches, we explored that the specific mutations in the UK (N501Y), South African (K417N-E484K-N501Y), Brazilian (K417T-E484K-N501Y), and hypothetical (N501Y-E484K) variants alter the binding affinity, create new inter-protein contacts and changes the internal structural dynamics thereby increases the binding and eventually the infectivity. Our investigation highlighted that the South African (K417N-E484K-N501Y), Brazilian (K417T-E484K-N501Y) variants are more lethal than the UK variant (N501Y). The behavior of the wild type and N501Y is comparable. Free energy calculations further confirmed that increased binding of the spike RBD to the ACE2 is mainly due to the electrostatic contribution. Further, we find that the unusual virulence of this virus is potentially the consequence of Darwinian selection-driven epistasis in protein evolution. The triple mutants (South African and Brazilian) may pose a serious threat to the efficacy of the already developed vaccine. Our analysis would help to understand the binding and structural dynamics of the new mutations in the RBD domain of the Spike protein and demand further investigation in in vitro and in vivo models to design potential therapeutics against the new variants.