SARS-CoV-2 Spike Protein Unlikely to Bind to Integrins via the Arg-Gly-Asp (RGD) Motif of the Receptor Binding Domain: Evidence From Structural Analysis and Microscale Accelerated Molecular Dynamics

  1. Houcemeddine Othman
  2. Haifa Ben Messaoud
  3. Oussema Khamessi
  4. Hazem Ben-Mabrouk
  5. Kais Ghedira
  6. Avani Bharuthram
  7. Florette Treurnicht
  8. Ikechukwu Achilonu
  9. Yasien Sayed
  10. Najet Srairi-Abid

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Abstract

The Receptor Binding Domain (RBD) of SARS-CoV-2 virus harbors a sequence of Arg-Gly-Asp tripeptide named RGD motif, which has also been identified in extracellular matrix proteins that bind integrins as well as other disintegrins and viruses. Accordingly, integrins have been proposed as host receptors for SARS-CoV-2. However, given that the microenvironment of the RGD motif imposes a structural hindrance to the protein-protein association, the validity of this hypothesis is still uncertain. Here, we used normal mode analysis, accelerated molecular dynamics microscale simulation, and protein-protein docking to investigate the putative role of RGD motif of SARS-CoV-2 RBD for interacting with integrins. We found, that neither RGD motif nor its microenvironment showed any significant conformational shift in the RBD structure. Highly populated clusters of RBD showed no capability to interact with the RGD binding site in integrins. The free energy landscape revealed that the RGD conformation within RBD could not acquire an optimal geometry to allow the interaction with integrins. In light of these results, and in the event where integrins are confirmed to be host receptors for SARS-CoV-2, we suggest a possible involvement of other residues to stabilize the interaction.

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  1. Version published to 10.3389/fmolb.2022.834857
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    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    For this study, the Bio3D package in R (version 2.4-1.9000) was utilized to conduct a comparative NMA analysis of a large ensemble of structures [22].
    Bio3D
    suggested: None
    Clustering analysis was executed using a hierarchical algorithm embedded in the ‘cpptraj’ analysis tool implemented by AMBER.
    AMBER
    suggested: (AMBER, RRID:SCR_016151)

    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.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.05.24.445335v1 on bioRxiv