Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 120-752, Korea.
Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 120-752, Korea.
Viruses. 2021 Nov 17;13(11):2295. doi: 10.3390/v13112295.
The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these "variants of concern" has increased immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (kappa and delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.
新型 SARS-CoV-2 变体的出现威胁到了控制 COVID-19 大流行的努力。这些“关注变体”的出现增加了免疫逃逸能力，并取代了祖先株。B.1.617 谱系（kappa 和 delta）携带的新型变体在刺突（S）蛋白的受体结合域内携带突变（L452R + E484Q 和 L452R + T478K），该区域与宿主受体结合。这些新型变体携带的双重突变主要导致印度 COVID-19 病例数量激增。在这项研究中，我们彻底研究了这些双重突变对与人类宿主受体结合能力的影响。我们进行了几项结构分析，发现研究中的双重突变增加了刺突蛋白与人类宿主受体（ACE2）的结合亲和力。此外，我们的研究表明，这些双突变体可能是增强 SARS-CoV-2 受体结合亲和力的主要贡献者，从而使其更稳定。我们还研究了这些突变对两种单克隆抗体（Abs）（2-15 和 LY-CoV555）结合亲和力的影响，发现双重突变的存在也阻碍了其与研究 Abs 的结合。主成分分析、自由能景观、分子间相互作用和其他研究提供了更深入的结构见解，以更好地理解导致这些变体病毒传染性增加的分子机制。
