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Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2

Fang Tian, Bei Tong, Liang Sun, Shengchao Shi, Bin Zheng, Zibin Wang, Xianchi Dong, View ORCID ProfilePeng Zheng
doi: https://doi.org/10.1101/2021.02.14.431117
Fang Tian
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, China
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Bei Tong
2Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing, 210014, China
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  • For correspondence: pengz@nju.edu.cn beitong@cnbg.net xianchidong@nju.edu.cn
Liang Sun
3State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
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Shengchao Shi
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, China
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Bin Zheng
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, China
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Zibin Wang
3State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
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Xianchi Dong
3State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210023, China
4Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, China
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  • For correspondence: pengz@nju.edu.cn beitong@cnbg.net xianchidong@nju.edu.cn
Peng Zheng
1State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu, 210023, China
4Engineering Research Center of Protein and Peptide Medicine, Ministry of Education, China
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  • ORCID record for Peng Zheng
  • For correspondence: pengz@nju.edu.cn beitong@cnbg.net xianchidong@nju.edu.cn
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ABSTRACT

Coronavirus disease-19 (COVID-19) is spreading around the world for the past year. Enormous efforts have been taken to understand its mechanism of transmission. It is well established now that the SARS-CoV-2 receptor-binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) as its first step of entry. Being a single-stranded RNA virus, SARS-CoV-2 is evolving rapidly. Recently, two variants, B.1.1.7 and B.1.351, both with a key mutation N501Y on the RBD, appear to be more infectious to humans. To understand its mechanism, we combined kinetics assay, single-molecule technique, and computational method to compare the interaction between these RBD (mutations) and ACE2. Remarkably, RBD with the N501Y mutation exhibited a considerably stronger interaction characterized from all these methodologies, while the other two mutations from B.1.351 contributed to a less effect. Surface plasmon resonance and fluorescence-activated cell scan (FACS) assays found that both RBD mutations are of higher binding affinity to ACE2 than the wild type. In addition, atomic force microscopy-based single-molecule force microscopy quantify their strength on living cells, showing a higher binding probability and unbinding force for both mutations. Finally, Steered Molecular Dynamics (SMD) simulations on the dissociation of RBD-ACE2 complexes revealed the possible structural details for the higher force/interaction. Taking together, we suggested that the stronger interaction from N501Y mutation in RBD should play an essential role in the higher transmission of COVID-19 variants.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviation

    COVID-19
    coronavirus disease-19
    SARS-CoV-2
    Severe Acute Respiratory Syndrome coronavirus-2
    MERS-CoV
    Middle East Respiratory Syndrome coronavirus
    RBD
    Receptor-Binding Domain
    ACE2
    Angiotensin-Converting Enzyme 2
    SPR
    Surface Plasmon Resonance
    FACS
    Fluorescence-activated cell Scan
    AFM
    Atomic Force Microscopy
    SMFS
    Single-molecule force spectroscopy
    SMD
    Steered Molecular Dynamics
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    Posted February 15, 2021.
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    Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2
    Fang Tian, Bei Tong, Liang Sun, Shengchao Shi, Bin Zheng, Zibin Wang, Xianchi Dong, Peng Zheng
    bioRxiv 2021.02.14.431117; doi: https://doi.org/10.1101/2021.02.14.431117
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    Mutation N501Y in RBD of Spike Protein Strengthens the Interaction between COVID-19 and its Receptor ACE2
    Fang Tian, Bei Tong, Liang Sun, Shengchao Shi, Bin Zheng, Zibin Wang, Xianchi Dong, Peng Zheng
    bioRxiv 2021.02.14.431117; doi: https://doi.org/10.1101/2021.02.14.431117

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