Computational Hot‐Spot Analysis of the SARS‐CoV‐2 Receptor Binding Domain/ACE2 Complex**

  1. Pedro A. Rosario
  2. Brian R. McNaughton

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Abstract

Infection and replication of SARS CoV‐2 (the virus that causes COVID‐19) requires entry to the interior of host cells. In humans, a protein–protein interaction (PPI) between the SARS CoV‐2 receptor‐binding domain (RBD) and the extracellular peptidase domain of ACE2 on the surface of cells in the lower respiratory tract is an initial step in the entry pathway. Inhibition of the SARS CoV‐2 RBD/ACE2 PPI is currently being evaluated as a target for therapeutic and/or prophylactic intervention. However, relatively little is known about the molecular underpinnings of this complex. Employing multiple computational platforms, we predicted “hot‐spot” residues in a positive‐control PPI (PMI/MDM2) and the CoV‐2 RBD/ACE2 complex. Computational alanine scanning mutagenesis was performed to predict changes in Gibbs’ free energy that are associated with mutating residues at the positive control (PMI/MDM2) or SARS RBD/ACE2 binding interface to alanine. Additionally, we used the Adaptive Poisson‐Boltzmann Solver to calculate macromolecular electrostatic surfaces at the interface of the positive‐control PPI and SARS CoV‐2/ACE2 PPI. Finally, a comparative analysis of hot‐spot residues for SARS‐CoV and SARS‐CoV‐2, in complex with ACE2, is provided. Collectively, this study illuminates predicted hot‐spot residues, and clusters, at the SARS CoV‐2 RBD/ACE2 binding interface, potentially guiding the development of reagents capable of disrupting this complex and halting COVID‐19.

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  1. Version published to 10.1002/cbic.202000562
  2. ScreenIT

    SciScore for 10.1101/2020.08.06.240333: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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: 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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  3. Version published to 10.1101/2020.08.06.240333v1 on bioRxiv