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.
Highlights
The molecular mechanism of human infection with SARS-CoV2 has been studied extensively (Shang et al, 2020a; Harrison et al, 2020; Li et al, 2021)
We found that the Root Mean Squared Inner Product (RMSIP) values are ranged from 0.86 to 1 (Figure 1E) which shows a high level of similarity and agrees with the results from the Principal Component Analysis (PCA) calculated from the normal modes
When we superposed the RGD motif from the Receptor Binding Domains (RBD) domain of SARS-CoV-2 with its corresponding sequence on the cilengitide molecule co-crystallized with the integrin, we found that severe clashes persist in this mode of interaction
Summary
The molecular mechanism of human infection with SARS-CoV2 has been studied extensively (Shang et al, 2020a; Harrison et al, 2020; Li et al, 2021). Sigrist et al (2020) have identified an Arg-Gly-Asp (RGD) motif in the sequence of the spike RBD which is found to be exposed at the surface of the interaction domain. This motif was originally identified within the extracellular matrix proteins, including fibronectin, fibrinogen, vitronectin, and laminin that mediate cell attachment. Α2β1, a collagen and laminin receptor, play a critical role in cell infection by echovirus (Eisner, 1992) Based on these findings, Sigrist et al (2020) concluded that integrins can interact with the spike protein. To investigate the extent of such effect on the RGD/ RBD conformational and binding properties, we conducted a computational study involving microscale accelerated molecular dynamics simulation and protein-protein docking
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