tetano
Editor, Senior Moderator
Comput Struct Biotechnol J
. 2022;20:6302-6316.
doi: 10.1016/j.csbj.2022.11.004. Epub 2022 Nov 7.
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[SUP] 1 2 [/SUP], Vaishali P Waman[SUP] 1 [/SUP], Franca Fraternali[SUP] 1 [/SUP], Christine Orengo[SUP] 1 [/SUP], Jonathan Lees[SUP] 3 4 [/SUP]
Affiliations
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.
. 2022;20:6302-6316.
doi: 10.1016/j.csbj.2022.11.004. Epub 2022 Nov 7.
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[SUP] 1 2 [/SUP], Vaishali P Waman[SUP] 1 [/SUP], Franca Fraternali[SUP] 1 [/SUP], Christine Orengo[SUP] 1 [/SUP], Jonathan Lees[SUP] 3 4 [/SUP]
Affiliations
- PMID: 36408455
- PMCID: PMC9639386
- DOI: 10.1016/j.csbj.2022.11.004
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.