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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.

Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain. Thumbnail


Authors

Zachariah P. Schuurs

Edward Hammond

Stefano Elli

Timothy R. Rudd

Courtney J. Mycroft-West

Richard Karlsson

Yen-Hsi Chen

Ieva Bagdonaite

Zhang Yang

Yassir A. Ahmed

Derek J. Richard

Vito Ferro

Deirdre R. Coombe

Neha S. Gandhi



Abstract

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 Article
Acceptance Date May 1, 2021
Publication Date 2021
Publicly Available Date May 30, 2023
Journal Computational and Structural Biotechnology Journal
Print ISSN 2001-0370
Publisher Research Network of Computational and Structural Biotechnology
Volume 19
Pages 2806 - 2818
DOI https://doi.org/10.1016/j.csbj.2021.05.002
Keywords COVID-19, Coronavirus, Cosolvent MD simulations, Heparan sulfate, Heparin, SARS-CoV-2, Spike protein
Publisher URL https://www.sciencedirect.com/science/article/pii/S2001037021001835?via%3Dihub

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