Zachariah P. Schuurs
Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain.
Schuurs, Zachariah P.; Hammond, Edward; Elli, Stefano; Rudd, Timothy R.; Mycroft-West, Courtney J.; Lima, Marcelo A.; Skidmore, Mark A.; Karlsson, Richard; Chen, Yen-Hsi; Bagdonaite, Ieva; Yang, Zhang; Ahmed, Yassir A.; Richard, Derek J.; Turnbull, Jeremy; Ferro, Vito; Coombe, Deirdre R.; Gandhi, Neha S.
Timothy R. Rudd
Courtney J. Mycroft-West
Marcelo Andrade De Lima email@example.com
Mark Skidmore firstname.lastname@example.org
Yassir A. Ahmed
Derek J. Richard
Jeremy Turnbull email@example.com
Deirdre R. Coombe
Neha S. Gandhi
SARS-CoV-2 has rapidly spread throughout the world's population since its initial discovery in 2019. The virus infects cells via a glycosylated spike protein located on its surface. The protein primarily binds to the angiotensin-converting enzyme-2 (ACE2) receptor, using glycosaminoglycans (GAGs) as co-receptors. Here, we performed bioinformatics and molecular dynamics simulations of the spike protein to investigate the existence of additional GAG binding sites on the receptor-binding domain (RBD), separate from previously reported heparin-binding sites. A putative GAG binding site in the N-terminal domain (NTD) of the protein was identified, encompassing residues 245-246. We hypothesized that GAGs of a sufficient length might bridge the gap between this site and the PRRARS furin cleavage site, including the mutation S247R. Docking studies using GlycoTorch Vina and subsequent MD simulations of the spike trimer in the presence of dodecasaccharides of the GAGs heparin and heparan sulfate supported this possibility. The heparan sulfate chain bridged the gap, binding the furin cleavage site and S247R. In contrast, the heparin chain bound the furin cleavage site and surrounding glycosylation structures, but not S247R. These findings identify a site in the spike protein that favors heparan sulfate binding that may be particularly pertinent for a better understanding of the recent UK and South African strains. This will also assist in future targeted therapy programs that could include repurposing clinical heparan sulfate mimetics.
|Journal Article Type
|May 1, 2021
|Publicly Available Date
|May 30, 2023
|Computational and Structural Biotechnology Journal
|Research Network of Computational and Structural Biotechnology
|2806 - 2818
|COVID-19, Coronavirus, Cosolvent MD simulations, Heparan sulfate, Heparin, SARS-CoV-2, Spike protein
Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain.pdf
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