Elucidating the differences in the molecular mechanism of receptor binding between 2019-nCoV and the SARS-CoV viruses using computational tools

  1. Hien T. T. Lai
  2. Ly H. Nguyen
  3. Agata Kranjc
  4. Toan T. Nguyen
  5. Duc Nguyen-Manh

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Abstract

The outbreak of the 2019-nCoV coronavirus causing severe acute respiratory syndrome which can be fatal, especially in elderly population, has been declared a pandemic by the World Health Organization. Many biotechnology laboratories are rushing to develop therapeutic antibodies and antiviral drugs for treatment of this viral disease. The viral CoV spike (S) glycoprotein is one of the main targets for pharmacological intervention. Its receptor-binding domain (RBD) interacts with the human ACE2 receptor ensuring the entry of the viral genomes into the host cell. In this work, we report on the differences in the binding of the RBD of the previous coronavirus SARS-CoV and of the newer 2019-nCoV coronavirus to the human ACE2 receptor using atomistic molecular dynamics techniques. Our results show major mutations in the 2019-nCoV RBD with respect to the SARS-CoV RBD occurring at the interface of RBD-ACE2 complex. These mutations make the 2019-nCoV RBD protein backbone much more flexible, hydrophobic interactions are reduced and additional polar/charged residues appear at the interface. We observe that higher flexibility of the 2019-nCoV RBD with respect to the SARS-CoV RBD leads to a bigger binding interface between the 2019-nCoV RBD and ACE2 and to about 20% more contacts between them in comparison with SARS-CoV. Taken together, the 2019-nCoV RBD shows more stable binding interface and higher binding affinity for the ACE2 receptor. The mutations not only stabilize the binding interface, they also lead to overall more stable 2019-nCoV RBD protein structure, even far from the binding interface. Our results on the molecular differences in the binding between the two viruses can provide important inputs for development of appropriate antiviral treatments of the new viruses, addressing the necessity of ongoing pandemics.

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    SciScore for 10.1101/2020.04.21.053009: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The RBD - ACE2 complexes were obtained from the RCSB PDB database with ID: 6VW1,25 6M0J26 for the new SARS-CoV-2 viruses, and 2AJF24 for the SARS-CoV virus.
    ID
    suggested: (IDBS, RRID:SCR_004077)
    For alignment of the primary sequences of the proteins, ClustalW web-server29 with BLO-SUM matrix,30 BioEdit software31 are used.
    ClustalW
    suggested: (ClustalW, RRID:SCR_017277)
    BioEdit
    suggested: (BioEdit, RRID:SCR_007361)
    Molecular Dynamics (MD) simulations36 are performed on the systems using the GROMACS/2018.6 software package.
    GROMACS/2018.6
    suggested: None
    Standard analyses such as mean deviation, mean fluctuation, hydrogen bonding are performed using GROMACS software.
    GROMACS
    suggested: (GROMACS, RRID:SCR_014565)
    SciPy python package is used for calculating probability density, Gaussian quadrature from which the difference in the binding free energy of the proteins is estimated.
    SciPy
    suggested: (SciPy, RRID:SCR_008058)
    python
    suggested: (IPython, RRID:SCR_001658)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.04.21.053009v1 on bioRxiv