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Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data.
J Cell Physiol. 2021 10; 236(10):7045-7057.JC

Abstract

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.

Authors+Show Affiliations

Department of Bioinformatics and Biological Statistics, Shanghai Jiao Tong University, Shanghai, P.R. China.Department of Microbiology, Quaid-i-Azam University, Islamabad, Pakistan.Center for Biotechnology and Microbiology, University of Swat, Swat, Khyber-Pakhtunkhwa, Pakistan.Department of Bioinformatics and Biological Statistics, Shanghai Jiao Tong University, Shanghai, P.R. China.Center for Biotechnology and Microbiology, University of Swat, Swat, Khyber-Pakhtunkhwa, Pakistan.National Center for Bioinformatics, Quaid-i-Azam University, Islamabad, Pakistan.Department of Biochemistry and Molecular Biology, Dasman Diabetes Institute, Kuwait.Department of Bioinformatics and Biological Statistics, Shanghai Jiao Tong University, Shanghai, P.R. China. State Key Laboratory of Microbial Metabolism, Shanghai-Islamabad-Belgrade Joint Innovation Center on Antibacterial Resistances, Joint Laboratory of International Laboratory of Metabolic and Developmental Sciences, Ministry of Education and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, P.R. China. Peng Cheng Laboratory, Vanke Cloud City Phase I Building 8, Xili Street, Nashan District, Guangdong, Shenzhen, P.R. China.

Pub Type(s)

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

Language

eng

PubMed ID

33755190

Citation

Khan, Abbas, et al. "Higher Infectivity of the SARS-CoV-2 New Variants Is Associated With K417N/T, E484K, and N501Y Mutants: an Insight From Structural Data." Journal of Cellular Physiology, vol. 236, no. 10, 2021, pp. 7045-7057.
Khan A, Zia T, Suleman M, et al. Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data. J Cell Physiol. 2021;236(10):7045-7057.
Khan, A., Zia, T., Suleman, M., Khan, T., Ali, S. S., Abbasi, A. A., Mohammad, A., & Wei, D. Q. (2021). Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data. Journal of Cellular Physiology, 236(10), 7045-7057. https://doi.org/10.1002/jcp.30367
Khan A, et al. Higher Infectivity of the SARS-CoV-2 New Variants Is Associated With K417N/T, E484K, and N501Y Mutants: an Insight From Structural Data. J Cell Physiol. 2021;236(10):7045-7057. PubMed PMID: 33755190.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Higher infectivity of the SARS-CoV-2 new variants is associated with K417N/T, E484K, and N501Y mutants: An insight from structural data. AU - Khan,Abbas, AU - Zia,Tauqir, AU - Suleman,Muhammad, AU - Khan,Taimoor, AU - Ali,Syed Shujait, AU - Abbasi,Aamir Ali, AU - Mohammad,Anwar, AU - Wei,Dong-Qing, Y1 - 2021/03/23/ PY - 2021/03/01/revised PY - 2021/01/28/received PY - 2021/03/04/accepted PY - 2021/3/24/pubmed PY - 2021/9/9/medline PY - 2021/3/23/entrez KW - KD (dissociation constant) KW - MD simulation KW - SARS-CoV-2 KW - new variants KW - protein-protein docking SP - 7045 EP - 7057 JF - Journal of cellular physiology JO - J Cell Physiol VL - 236 IS - 10 N2 - 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. SN - 1097-4652 UR - https://www.unboundmedicine.com/medline/citation/33755190/Higher_infectivity_of_the_SARS_CoV_2_new_variants_is_associated_with_K417N/T_E484K_and_N501Y_mutants:_An_insight_from_structural_data_ DB - PRIME DP - Unbound Medicine ER -