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Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity.
Int J Mol Sci. 2021 Aug 24; 22(17)IJ

Abstract

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2.

Authors+Show Affiliations

Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India.Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India.Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India. Department of Life Science, School of Basic Sciences and Research, Sharda University, Greater Noida 201301, India.Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology (IIT) Delhi, New Delhi 110016, India.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34502041

Citation

Kumar, Vipul, et al. "Possible Link Between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity." International Journal of Molecular Sciences, vol. 22, no. 17, 2021.
Kumar V, Singh J, Hasnain SE, et al. Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity. Int J Mol Sci. 2021;22(17).
Kumar, V., Singh, J., Hasnain, S. E., & Sundar, D. (2021). Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity. International Journal of Molecular Sciences, 22(17). https://doi.org/10.3390/ijms22179131
Kumar V, et al. Possible Link Between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity. Int J Mol Sci. 2021 Aug 24;22(17) PubMed PMID: 34502041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Possible Link between Higher Transmissibility of Alpha, Kappa and Delta Variants of SARS-CoV-2 and Increased Structural Stability of Its Spike Protein and hACE2 Affinity. AU - Kumar,Vipul, AU - Singh,Jasdeep, AU - Hasnain,Seyed E, AU - Sundar,Durai, Y1 - 2021/08/24/ PY - 2021/07/13/received PY - 2021/08/20/revised PY - 2021/08/22/accepted PY - 2021/9/10/entrez PY - 2021/9/11/pubmed PY - 2021/9/15/medline KW - B.1.1.7 KW - B.1.617.2 KW - COVID-19 KW - E484Q KW - N501Y mutation KW - T478K and L452R mutation KW - spike protein JF - International journal of molecular sciences JO - Int J Mol Sci VL - 22 IS - 17 N2 - The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak in December 2019 has caused a global pandemic. The rapid mutation rate in the virus has created alarming situations worldwide and is being attributed to the false negativity in RT-PCR tests. It has also increased the chances of reinfection and immune escape. Recently various lineages namely, B.1.1.7 (Alpha), B.1.617.1 (Kappa), B.1.617.2 (Delta) and B.1.617.3 have caused rapid infection around the globe. To understand the biophysical perspective, we have performed molecular dynamic simulations of four different spikes (receptor binding domain)-hACE2 complexes, namely wildtype (WT), Alpha variant (N501Y spike mutant), Kappa (L452R, E484Q) and Delta (L452R, T478K), and compared their dynamics, binding energy and molecular interactions. Our results show that mutation has caused significant increase in the binding energy between the spike and hACE2 in Alpha and Kappa variants. In the case of Kappa and Delta variants, the mutations at L452R, T478K and E484Q increased the stability and intra-chain interactions in the spike protein, which may change the interaction ability of neutralizing antibodies to these spike variants. Further, we found that the Alpha variant had increased hydrogen interaction with Lys353 of hACE2 and more binding affinity in comparison to WT. The current study provides the biophysical basis for understanding the molecular mechanism and rationale behind the increase in the transmissivity and infectivity of the mutants compared to wild-type SARS-CoV-2. SN - 1422-0067 UR - https://www.unboundmedicine.com/medline/citation/34502041/Possible_Link_between_Higher_Transmissibility_of_Alpha_Kappa_and_Delta_Variants_of_SARS_CoV_2_and_Increased_Structural_Stability_of_Its_Spike_Protein_and_hACE2_Affinity_ L2 - https://www.mdpi.com/resolver?pii=ijms22179131 DB - PRIME DP - Unbound Medicine ER -