Structural and energetic analyses of SARS-CoV-2 N-terminal domain characterise sugar binding pockets and suggest putative impacts of variants on COVID-19 transmission

Su Datt Lam; Vaishali P Waman; Franca Fraternali; Christine Orengo; Jonathan Lees

doi:10.1016/j.csbj.2022.11.004

Structural and energetic analyses of SARS-CoV-2 N-terminal domain characterise sugar binding pockets and suggest putative impacts of variants on COVID-19 transmission

Comput Struct Biotechnol J. 2022:20:6302-6316. doi: 10.1016/j.csbj.2022.11.004. Epub 2022 Nov 7.

Authors

Su Datt Lam^{1

2}, Vaishali P Waman¹, Franca Fraternali¹, Christine Orengo¹, Jonathan Lees^{3

4}

Affiliations

¹ Institute of Structural and Molecular Biology, University College London, London, United Kingdom.
² Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia.
³ Translational Health Sciences, Bristol Medical University, University of Bristol, Bristol, United Kingdom.
⁴ Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom.

Abstract

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is an ongoing pandemic that causes significant health/socioeconomic burden. Variants of concern (VOCs) have emerged affecting transmissibility, disease severity and re-infection risk. Studies suggest that the - N-terminal domain (NTD) of the spike protein may have a role in facilitating virus entry via sialic-acid receptor binding. Furthermore, most VOCs include novel NTD variants. Despite global sequence and structure similarity, most sialic-acid binding pockets in NTD vary across coronaviruses. Our work suggests ongoing evolutionary tuning of the sugar-binding pockets and recent analyses have shown that NTD insertions in VOCs tend to lie close to loops. We extended the structural characterisation of these sugar-binding pockets and explored whether variants could enhance sialic acid-binding. We found that recent NTD insertions in VOCs (i.e., Gamma, Delta and Omicron variants) and emerging variants of interest (VOIs) (i.e., Iota, Lambda and Theta variants) frequently lie close to sugar-binding pockets. For some variants, including the recent Omicron VOC, we find increases in predicted sialic acid-binding energy, compared to the original SARS-CoV-2, which may contribute to increased transmission. These binding observations are supported by molecular dynamics simulations (MD). We examined the similarity of NTD across Betacoronaviruses to determine whether the sugar-binding pockets are sufficiently similar to be exploited in drug design. Whilst most pockets are too structurally variable, we detected a previously unknown highly structurally conserved pocket which can be investigated in pursuit of a generic pan-Betacoronavirus drug. Our structure-based analyses help rationalise the effects of VOCs and provide hypotheses for experiments. Our findings suggest a strong need for experimental monitoring of changes in NTD of VOCs.

Keywords: SARS-CoV-2; Sialic acid-binding pocket; Spike N-terminal domain; Structural and functional impacts; Variants of concern.

Abstract

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