4.6 Article

Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage on the Human ACE2 Receptor Binding: A Structural Insight

期刊

VIRUSES-BASEL
卷 13, 期 11, 页码 -

出版社

MDPI
DOI: 10.3390/v13112295

关键词

SARS-CoV-2; COVID-19; variant; molecular dynamics; double mutant; delta variant; kappa variant

类别

资金

  1. National Research Foundation, Korea [NRF-2020K1A3A1A47110859]
  2. Taif University, Taif, Saudi Arabia [TURSP2020/310]
  3. National Research Foundation of Korea [2020K1A3A1A47110859] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

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The novel SARS-CoV-2 variants from the B.1.617 lineage (kappa and delta) carry double mutations that enhance their binding capability to the human host receptor, while also affecting their binding with monoclonal antibodies. The study suggests that these double mutants might be the main contributors to the surge in COVID-19 cases.
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.

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