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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.
Viruses. 2021 11 17; 13(11)V

Abstract

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.

Authors+Show Affiliations

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.Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, 41345 Gothenburg, Sweden.Department of Biotechnology, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.Department of Family 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.Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 120-752, Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34835101

Citation

Khan, Mohd Imran, et al. "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." Viruses, vol. 13, no. 11, 2021.
Khan MI, Baig MH, Mondal T, et al. 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. Viruses. 2021;13(11).
Khan, M. I., Baig, M. H., Mondal, T., Alorabi, M., Sharma, T., Dong, J. J., & Cho, J. Y. (2021). 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. Viruses, 13(11). https://doi.org/10.3390/v13112295
Khan MI, et al. 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. Viruses. 2021 11 17;13(11) PubMed PMID: 34835101.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Khan,Mohd Imran, AU - Baig,Mohammad Hassan, AU - Mondal,Tanmoy, AU - Alorabi,Mohammed, AU - Sharma,Tanuj, AU - Dong,Jae-June, AU - Cho,Jae Yong, Y1 - 2021/11/17/ PY - 2021/09/27/received PY - 2021/11/09/revised PY - 2021/11/11/accepted PY - 2021/11/27/entrez PY - 2021/11/28/pubmed PY - 2021/12/15/medline KW - COVID-19 KW - SARS-CoV-2 KW - delta variant KW - double mutant KW - kappa variant KW - molecular dynamics KW - variant JF - Viruses JO - Viruses VL - 13 IS - 11 N2 - 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. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/34835101/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_ L2 - https://www.mdpi.com/resolver?pii=v13112295 DB - PRIME DP - Unbound Medicine ER -