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RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility through Enhanced Interaction between RBD and ACE2 Receptor.
Viruses. 2021 12 21; 14(1)V

Abstract

The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant evolution of SARS-CoV-2 generates new mutations across its genome including the coding region for the RBD in the spike protein. In addition to the well-known single mutation in the RBD, the recent new mutation strains with an RBD "double mutation" are causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of double-mutated strains could be attributed to the altered interaction between the RBD and ACE2 receptor, the molecular details remain to be elucidated. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation, and antibody escaping, we investigated the relationship between the ACE2 receptor and the RBD double mutants of L452R/T478K (delta), L452R/E484Q (kappa), and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered the RBD structure and enhanced the binding of the mutated RBD to ACE2 receptor. Together with the mutations in other parts of the virus genome, the double mutations increase the transmissibility of SARS-CoV-2 to host cells.

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Authors+Show Affiliations

Sinha S
MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Taipa, Macau 999087, China.
Tam B
MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Taipa, Macau 999087, China.
Wang SM
MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, University of Macau, Taipa, Macau 999087, China.

MeSH

Angiotensin-Converting Enzyme 2Binding SitesCOVID-19HumansImmune EvasionMolecular Dynamics SimulationMutationProtein BindingProtein ConformationSARS-CoV-2Spike Glycoprotein, CoronavirusThermodynamics

Pub Type(s)

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

Language

eng

PubMed ID

35062205

Citation

Sinha, Siddharth, et al. "RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility Through Enhanced Interaction Between RBD and ACE2 Receptor." Viruses, vol. 14, no. 1, 2021.
Sinha S, Tam B, Wang SM. RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility through Enhanced Interaction between RBD and ACE2 Receptor. Viruses. 2021;14(1).
Sinha, S., Tam, B., & Wang, S. M. (2021). RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility through Enhanced Interaction between RBD and ACE2 Receptor. Viruses, 14(1). https://doi.org/10.3390/v14010001
Sinha S, Tam B, Wang SM. RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility Through Enhanced Interaction Between RBD and ACE2 Receptor. Viruses. 2021 12 21;14(1) PubMed PMID: 35062205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - RBD Double Mutations of SARS-CoV-2 Strains Increase Transmissibility through Enhanced Interaction between RBD and ACE2 Receptor. AU - Sinha,Siddharth, AU - Tam,Benjamin, AU - Wang,San Ming, Y1 - 2021/12/21/ PY - 2021/11/11/received PY - 2021/11/28/revised PY - 2021/12/15/accepted PY - 2022/1/22/entrez PY - 2022/1/23/pubmed PY - 2022/2/4/medline KW - MM/GBSA KW - SARS-CoV-2 KW - antibody escape KW - free energy KW - md simulations KW - variants JF - Viruses JO - Viruses VL - 14 IS - 1 N2 - The COVID-19 pandemic, caused by SARS-CoV-2, has led to catastrophic damage for global human health. The initial step of SARS-CoV-2 infection is the binding of the receptor-binding domain (RBD) in its spike protein to the ACE2 receptor in the host cell membrane. Constant evolution of SARS-CoV-2 generates new mutations across its genome including the coding region for the RBD in the spike protein. In addition to the well-known single mutation in the RBD, the recent new mutation strains with an RBD "double mutation" are causing new outbreaks globally, as represented by the delta strain containing RBD L452R/T478K. Although it is considered that the increased transmissibility of double-mutated strains could be attributed to the altered interaction between the RBD and ACE2 receptor, the molecular details remain to be elucidated. Using the methods of molecular dynamics simulation, superimposed structural comparison, free binding energy estimation, and antibody escaping, we investigated the relationship between the ACE2 receptor and the RBD double mutants of L452R/T478K (delta), L452R/E484Q (kappa), and E484K/N501Y (beta, gamma). The results demonstrated that each of the three RBD double mutants altered the RBD structure and enhanced the binding of the mutated RBD to ACE2 receptor. Together with the mutations in other parts of the virus genome, the double mutations increase the transmissibility of SARS-CoV-2 to host cells. SN - 1999-4915 UR - https://www.unboundmedicine.com/medline/citation/35062205/RBD_Double_Mutations_of_SARS_CoV_2_Strains_Increase_Transmissibility_through_Enhanced_Interaction_between_RBD_and_ACE2_Receptor_ DB - PRIME DP - Unbound Medicine ER -