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 ORCID: 0000-0003-4434-0333, Mycroft-West, Courtney J, Lima, Marcelo A, Skidmore, Mark A, Karlsson, Richard, Chen, Yen-Hsi, Bagdonaite, Ieva
et al (show 7 more authors) (2021) Evidence of a putative glycosaminoglycan binding site on the glycosylated SARS-CoV-2 spike protein N-terminal domain. COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL, 19. pp. 2806-2818.

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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.

Item Type: Article
Uncontrolled Keywords: Heparan sulfate, SARS-CoV-2, COVID-19, Spike protein, Heparin, Coronavirus, Cosolvent MD simulations
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 23 Dec 2021 08:57
Last Modified: 18 Jan 2023 21:18
DOI: 10.1016/j.csbj.2021.05.002
Open Access URL: https://doi.org/10.1016/j.csbj.2021.05.002
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3145946