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

Houcemeddine Othman; Haifa Ben Messaoud; Oussema Khamessi; Hazem Ben-Mabrouk; Kais Ghedira; Avani Bharuthram; Florette Treurnicht; Ikechukwu Achilonu; Yasien Sayed; Najet Srairi-Abid

doi:10.3389/fmolb.2022.834857

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

Front Mol Biosci. 2022 Feb 14:9:834857. doi: 10.3389/fmolb.2022.834857. eCollection 2022.

Authors

Affiliations

¹ Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
² Laboratory of Biomolecules, Venoms and Theranostic Applications, LR20IPT01, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis, Tunisia.
³ National Gene Bank of Tunisia, Boulevard du Leader Yesser Arafet, Tunis, Tunisia.
⁴ Université de Tunis El Manar, Institut Pasteur de Tunis, LR11IPT08 Venins et Biomolecules Therapeutiques, Tunis, Tunisie.
⁵ Laboratory of Bioinformatics, Biomathematics and Biostatistics (BIMS), Institut Pasteur de Tunis (IPT), University of Tunis El Manar, Tunis, Tunisia.
⁶ Department of Virology, National Health Laboratory Services and the School of Pathology, University of the Witwatersrand, Johannesburg, South Africa.
⁷ Protein Structure-Function Research Unit, School of Molecular and Cell Biology, University of Witwatersrand, Johannesburg, South Africa.

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.

Keywords: COVID-19; RBD; SARS-CoV-2; integrin; molecular dynamcis.