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
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 s...
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Elsevier
2022-01-01
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Series: | Computational and Structural Biotechnology Journal |
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Online Access: | http://www.sciencedirect.com/science/article/pii/S2001037022004986 |
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author | Su Datt Lam Vaishali P. Waman Franca Fraternali Christine Orengo Jonathan Lees |
author_facet | Su Datt Lam Vaishali P. Waman Franca Fraternali Christine Orengo Jonathan Lees |
author_sort | Su Datt Lam |
collection | DOAJ |
description | 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. |
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language | English |
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spelling | doaj.art-59cb0131af0f4133984444ee80f831cc2022-12-24T04:55:03ZengElsevierComputational and Structural Biotechnology Journal2001-03702022-01-012063026316Structural and energetic analyses of SARS-CoV-2 N-terminal domain characterise sugar binding pockets and suggest putative impacts of variants on COVID-19 transmissionSu Datt Lam0Vaishali P. Waman1Franca Fraternali2Christine Orengo3Jonathan Lees4Institute of Structural and Molecular Biology, University College London, London, United Kingdom; Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia; Corresponding authors at: Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia (S.D. Lam); Institute of Structural and Molecular Biology, University College London, London, United Kingdom (C. Orengo); Translational Health Sciences, Bristol Medical University, University of Bristol, Bristol, United Kingdom (J. Lees)Institute of Structural and Molecular Biology, University College London, London, United KingdomInstitute of Structural and Molecular Biology, University College London, London, United KingdomInstitute of Structural and Molecular Biology, University College London, London, United Kingdom; Corresponding authors at: Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia (S.D. Lam); Institute of Structural and Molecular Biology, University College London, London, United Kingdom (C. Orengo); Translational Health Sciences, Bristol Medical University, University of Bristol, Bristol, United Kingdom (J. Lees)Translational Health Sciences, Bristol Medical University, University of Bristol, Bristol, United Kingdom; Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom; Corresponding authors at: Department of Applied Physics, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi, Malaysia (S.D. Lam); Institute of Structural and Molecular Biology, University College London, London, United Kingdom (C. Orengo); Translational Health Sciences, Bristol Medical University, University of Bristol, Bristol, United Kingdom (J. Lees)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.http://www.sciencedirect.com/science/article/pii/S2001037022004986SARS-CoV-2Sialic acid-binding pocketSpike N-terminal domainStructural and functional impactsVariants of concern |
spellingShingle | Su Datt Lam Vaishali P. Waman Franca Fraternali Christine Orengo Jonathan Lees 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 Computational and Structural Biotechnology Journal SARS-CoV-2 Sialic acid-binding pocket Spike N-terminal domain Structural and functional impacts Variants of concern |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | SARS-CoV-2 Sialic acid-binding pocket Spike N-terminal domain Structural and functional impacts Variants of concern |
url | http://www.sciencedirect.com/science/article/pii/S2001037022004986 |
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