High Throughput Designing and Mutational Mapping of RBD-ACE2 Interface Guide Non-Conventional Therapeutic Strategies for COVID-19

  1. Aditya K. Padhi
  2. Parismita Kalita
  3. Kam Y. J. Zhang
  4. Timir Tripathi

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Abstract

Considering the current status of the SARS-CoV-2 pandemic, sequence variations and possibly structural changes in the rapidly evolving SARS-CoV-2 is highly expected in the coming months. The SARS-CoV-2 spike (S) protein is responsible for mediating viral attachment and fusion with cell membranes. Mutations in the receptor-binding domain (RBD) of the S-protein occur at the most variable part of the SARS-CoV-2 genome, and specific sites of S-protein have undergone positive selection impacting the viral pathogenicity. In the present work, we used high-throughput computation to design 100,000 mutants in RBD interfacial residues and identify novel affinity-enhancing and affinity-weakening mutations. Our data suggest that SARS-CoV-2 can establish a higher rate of infectivity and pathogenesis when it acquires combinatorial mutations at the interfacial residues in RBD. Mapping of the mutational landscape of the interaction site suggests that a few of these residues are the hot-spot residues with a very high tendency to undergo positive selection. Knowledge of the affinity-enhancing mutations may guide the identification of potential cold-spots for this mutation as targets for developing a possible therapeutic strategy instead of hot-spots, and vice versa. Understanding of the molecular interactions between the virus and host protein presents a detailed systems view of viral infection mechanisms. The applications of the present research can be explored in multiple antiviral strategies, including monoclonal antibody therapy, vaccine design, and importantly in understanding the clinical pathogenesis of the virus itself. Our work presents research directions for the exploitation of non-conventional solutions for COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.05.19.104042: (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
    Sequence logos of top-ranked affinity-enhancing and affinity-weakening designs: The frequency and types of designed residues in the top-ranked affinity-enhancing and affinity-weakening designs were obtained and plotted using WebLogo that gives a graphical representation of an amino acid multiple sequence alignment [22].
    WebLogo
    suggested: (WEBLOGO, RRID:SCR_010236)
    Calculation of intermolecular interactions governing the affinity-enhancing and affinity-weakening mutants: The intermolecular interactions between ACE2 and RBD for the top-ranked affinity-enhancing and affinity-weakening designs were obtained using Arpeggio web-server [24].
    Arpeggio
    suggested: (Arpeggio, RRID:SCR_010876)
    As a final step, residue level interactions between ACE2 and RBD interface for the top-ranked affinity-enhancing and affinity-weakening designs obtained by the DIMPLOT program of LigPlot+v1.4.5 and were analyzed in Pymol.
    Pymol
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 19. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

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

    About SciScore

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  2. Version published to 10.1101/2020.05.19.104042v1 on bioRxiv