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Article: Fine-tuning the spike: role of the nature and topology of the glycan shield in the structure and dynamics of the SARS-CoV-2 S.

Harbison, Aoife M / Fogarty, Carl A / Phung, Toan K / Satheesan, Akash / Schulz, Benjamin L / Fadda, Elisa

2021 Volume 13, Issue 2, Page(s) 386–395

Abstract: The dense glycan shield is an essential feature of the SARS-CoV-2 spike (S) architecture, key to immune evasion and to the activation of the prefusion conformation. Recent studies indicate that the occupancy and structures of the SARS-CoV-2 S glycans ... ...

Abstract	The dense glycan shield is an essential feature of the SARS-CoV-2 spike (S) architecture, key to immune evasion and to the activation of the prefusion conformation. Recent studies indicate that the occupancy and structures of the SARS-CoV-2 S glycans depend not only on the nature of the host cell, but also on the structural stability of the trimer; a point that raises important questions about the relative competence of different glycoforms. Moreover, the functional role of the glycan shield in the SARS-CoV-2 pathogenesis suggests that the evolution of the sites of glycosylation is potentially intertwined with the evolution of the protein sequence to affect optimal activity. Our results from multi-microsecond molecular dynamics simulations indicate that the type of glycosylation at N234, N165 and N343 greatly affects the stability of the receptor binding domain (RBD) open conformation, and thus its exposure and accessibility. Furthermore, our results suggest that the loss of glycosylation at N370, a newly acquired modification in the SARS-CoV-2 S glycan shield's topology, may have contributed to increase the SARS-CoV-2 infectivity as we find that
Language	English
Publishing date	2021-11-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2559110-1
ISSN	2041-6539 ; 2041-6520
ISSN (online)	2041-6539
ISSN	2041-6520
DOI	10.1039/d1sc04832e
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: How and why plants and human N-glycans are different: Insight from molecular dynamics into the "glycoblocks" architecture of complex carbohydrates.

Fogarty, Carl A / Harbison, Aoife M / Dugdale, Amy R / Fadda, Elisa

Beilstein journal of organic chemistry

2020 Volume 16, Page(s) 2046–2056

Abstract: The N-glycosylation is one of the most abundant and diverse post-translational modifications of proteins, implicated in protein folding and structural stability, and mediating interactions with receptors and with the environment. All N-glycans share a ... ...

Abstract	The N-glycosylation is one of the most abundant and diverse post-translational modifications of proteins, implicated in protein folding and structural stability, and mediating interactions with receptors and with the environment. All N-glycans share a common core from which linear or branched arms stem from, with functionalization specific to different species and to the cells' health and disease state. This diversity generates a rich collection of structures, all diversely able to trigger molecular cascades and to activate pathways, which also include adverse immunogenic responses. These events are inherently linked to the N-glycans' 3D architecture and dynamics, which remain for the large part unresolved and undetected because of their intrinsic structural disorder. In this work we use molecular dynamics (MD) simulations to provide insight into N-glycans' 3D structure by analysing the effects of a set of very specific modifications found in plants and invertebrate N-glycans, which are immunogenic in humans. We also compare these structural motifs and combine them with mammalian N-glycan motifs to devise strategies for the control of the N-glycan 3D structure through sequence. Our results suggest that the N-glycans' architecture can be described in terms of the local spatial environment of groups of monosaccharides. We define these "glycoblocks" as self-contained 3D units, uniquely identified by the nature of the residues they comprise, their linkages and structural/dynamic features. This alternative description of glycans' 3D architecture can potentially lead to an easier prediction of sequence-to-structure relationships in complex carbohydrates, with important implications in glycoengineering design.
Language	English
Publishing date	2020-08-21
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2192461-2
ISSN	1860-5397
ISSN	1860-5397
DOI	10.3762/bjoc.16.171
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Article ; Online: #GotGlycans: Role of N343 Glycosylation on the SARS-CoV-2 S RBD Structure and Co-Receptor Binding Across Variants of Concern

Ives, Callum M. / Nguyen, Linh / Fogarty, Carl A. / Harbison, Aoife M. / Durocher, Yves / Klassen, John S. / Fadda, Elisa

bioRxiv

Abstract: Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also ... ...

Abstract	Glycosylation of the SARS-CoV-2 spike (S) protein represents a key target for viral evolution because it affects both viral evasion and fitness. Successful variations in the glycan shield are difficult to achieve though, as protein glycosylation is also critical to folding and to structural stability. Within this framework, the identification of glycosylation sites that are structurally dispensable can provide insight into the evolutionary mechanisms of the shield and inform immune surveillance. In this work we show through over 45 μs of cumulative sampling from conventional and enhanced molecular dynamics (MD) simulations, how the structure of the immunodominant S receptor binding domain (RBD) is regulated by N-glycosylation at N343 and how the structural role of this glycan changes from WHu-1, alpha (B.1.1.7), and beta (B.1.351), to the delta (B.1.617.2) and omicron (BA.1 and BA.2.86) variants. More specifically, we find that the amphipathic nature of the N-glycan is instrumental to preserve the structural integrity of the RBD hydrophobic core and that loss of glycosylation at N343 triggers a specific and consistent conformational change. We show how this change allosterically regulates the conformation of the receptor binding motif (RBM) in the WHu-1, alpha and beta RBDs, but not in the delta and omicron variants, due to mutations that reinforce the RBD architecture. In support of these findings, we show that the binding of the RBD to monosialylated ganglioside co-receptors is highly dependent on N343 glycosylation in the WHu-1, but not in the delta RBD, and that affinity changes significantly across VoCs. Ultimately, the molecular and functional insight we provide in this work reinforces our understanding of the role of glycosylation in protein structure and function and it also allows us to identify the structural constraints within which the glycosylation site at N343 can become a hotspot for mutations in the SARS-CoV-2 S glycan shield.
Keywords	covid19
Language	English
Publishing date	2023-12-05
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2023.12.05.570076
Database	COVID19

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Article ; Online: How and why plants and human N-glycans are different

Carl A. Fogarty / Aoife M. Harbison / Amy R. Dugdale / Elisa Fadda

Beilstein Journal of Organic Chemistry, Vol 16, Iss 1, Pp 2046-

Insight from molecular dynamics into the “glycoblocks” architecture of complex carbohydrates

2020 Volume 2056

Abstract	The N-glycosylation is one of the most abundant and diverse post-translational modifications of proteins, implicated in protein folding and structural stability, and mediating interactions with receptors and with the environment. All N-glycans share a common core from which linear or branched arms stem from, with functionalization specific to different species and to the cells’ health and disease state. This diversity generates a rich collection of structures, all diversely able to trigger molecular cascades and to activate pathways, which also include adverse immunogenic responses. These events are inherently linked to the N-glycans’ 3D architecture and dynamics, which remain for the large part unresolved and undetected because of their intrinsic structural disorder. In this work we use molecular dynamics (MD) simulations to provide insight into N-glycans’ 3D structure by analysing the effects of a set of very specific modifications found in plants and invertebrate N-glycans, which are immunogenic in humans. We also compare these structural motifs and combine them with mammalian N-glycan motifs to devise strategies for the control of the N-glycan 3D structure through sequence. Our results suggest that the N-glycans’ architecture can be described in terms of the local spatial environment of groups of monosaccharides. We define these “glycoblocks” as self-contained 3D units, uniquely identified by the nature of the residues they comprise, their linkages and structural/dynamic features. This alternative description of glycans’ 3D architecture can potentially lead to an easier prediction of sequence-to-structure relationships in complex carbohydrates, with important implications in glycoengineering design.
Keywords	complex carbohydrates ; fucose ; glycoblocks ; molecular dynamics ; molecular recognition ; n-glycans ; xylose ; Science ; Q ; Organic chemistry ; QD241-441
Subject code	612
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	Beilstein-Institut
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Sequence-to-structure dependence of isolated IgG Fc complex biantennary N-glycans: a molecular dynamics study.

Harbison, Aoife M / Brosnan, Lorna P / Fenlon, Keith / Fadda, Elisa

Glycobiology

2018 Volume 29, Issue 1, Page(s) 94–103

Abstract: Fc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function and inflammatory properties. Indeed, while ...

Abstract	Fc glycosylation of human immunoglobulins G (IgGs) is essential for their structural integrity and activity. Interestingly, the specific nature of the Fc glycoforms is known to modulate the IgG effector function and inflammatory properties. Indeed, while core-fucosylation of IgG Fc-glycans greatly affects the antibody-dependent cell-mediated cytotoxicity function, with obvious repercussions in the design of therapeutic antibodies, sialylation can reverse the antibody inflammatory response, and galactosylation levels have been linked to aging, to the onset of inflammation, and to the predisposition to rheumatoid arthritis. Within the framework of a structure-to-function relationship, we have studied the role of the N-glycan sequence on its intrinsic conformational propensity. Here we report the results of a systematic study, based on extensive molecular dynamics simulations in excess of 62 μs of cumulative simulation time, on the effect of sequence on the structure and dynamics of increasingly larger, complex biantennary N-glycoforms isolated from the protein, i.e. from chitobiose to the larger N-glycan species commonly found in the Fc region of human IgGs. Our results show that while core fucosylation and sialylation do not affect the intrinsic dynamics of the unlinked N-glycans, galactosylation of the α(1-6) arm shifts dramatically its conformational equilibrium from an outstretched to a folded conformation. These findings are in agreement with and can help rationalize recent experimental evidence showing a differential recognition of positional isomers in glycan array data and also the preference of sialyltransferase for the more accessible, outstretched α(1-3) arm in both isolated, and Fc-bound N-glycans.
MeSH term(s)	Humans ; Immunoglobulin Fc Fragments/chemistry ; Immunoglobulin G/chemistry ; Polysaccharides/chemistry ; Structure-Activity Relationship
Chemical Substances	Immunoglobulin Fc Fragments ; Immunoglobulin G ; Polysaccharides
Language	English
Publishing date	2018-07-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1067689-2
ISSN	1460-2423 ; 0959-6658
ISSN (online)	1460-2423
ISSN	0959-6658
DOI	10.1093/glycob/cwy097
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Article ; Online: Fine-tuning the Spike: Role of the nature and topology of the glycan shield in the structure and dynamics of SARS-CoV-2 S

Harbison, Aoife M. / Fogarty, Carl A. / Phung, Toan K. / Satheesan, Akash / Schulz, Benjamin L. / Fadda, Elisa

bioRxiv

Abstract: The SARS-CoV-2 spike (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID19. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein is not only essential for hiding the virus from ... ...

Abstract	The SARS-CoV-2 spike (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID19. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein is not only essential for hiding the virus from immune detection, but it also plays multiple functional roles, stabilising the S prefusion open conformation, which is competent for binding the ACE2 primary receptor, and gating the open-to-close transitions. This newly discovered functions of the glycan shield suggest the evolution of its sites of glycosylation is potentially intertwined with the evolution of the overall protein sequence to affect optimal activity. Furthermore, recent studies indicate that the occupancy and structures of SARS-CoV-2 S glycosylation depends not only on the host-cell, but also on the structural stability of the prefusion trimer; a point that raises important questions about the relative binding competence of different glycoforms. In this work we use multi-microsecond molecular dynamics simulations to characterize the structure and dynamics of different SARS-CoV-2 S models with different N-glycans at key functional sites, namely N234, N165 and N343. We also assessed the effect of a change in the SARS-CoV-2 S glycan shield topology at N370, due to the recently acquired T372A mutation. Our results indicate that the structures of the N-glycans at N234, N165 and N343 affect the stability of the active (or open) S conformation, and thus its exposure and accessibility. Furthermore, while glycosylation at N370 stabilizes the open S conformation, we find that the N370 glycan binds the closed receptor binding domain (RBD) surface, essentially tying the closed protomers together. These results suggest that the loss of the N370 glycosylation site in SARS-CoV-2 may have increased the availability of the open S form, perhaps contributing to its higher infectivity relative to CoV1 and other variants carrying the sequon. Finally, we discuss these specific changes to the topology of the SARS-CoV-2 S glycan shield through ancestral sequence reconstruction of select SARS strains and discuss how they may have evolved to affect S activity.
Keywords	covid19
Language	English
Publishing date	2021-04-01
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.01.438036
Database	COVID19

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Article ; Online: Fine-tuning the Spike: Role of the nature and topology of the glycan shield structure and dynamics of SARS-CoV-2 S

Harbison, Aoife M / Fogarty, Carl A / Phung, Toan K / Satheesan, Akash / Schulz, Benjamin L. / Fadda, Elisa

bioRxiv

Abstract	The SARS-CoV-2 spike (S) is a type I fusion glycoprotein, responsible for initiating the infection leading to COVID19. As a feature unique of SARS-CoV-2, the thick glycan shield covering the S protein is not only essential for hiding the virus from immune detection, but it also plays multiple functional roles, stabilising the S prefusion open conformation, which is competent for binding the ACE2 primary receptor, and gating the open-to-close transitions. This newly discovered functions of the glycan shield suggest the evolution of its sites of glycosylation is potentially intertwined with the evolution of the overall protein sequence to affect optimal activity. Furthermore, recent studies indicate that the occupancy and structures of SARS-CoV-2 S glycosylation depends not only on the host-cell, but also on the structural stability of the prefusion trimer; a point that raises important questions about the relative binding competence of different glycoforms. In this work we use multi-microsecond molecular dynamics simulations to characterize the structure and dynamics of different SARS-CoV-2 S models with different N-glycans at key functional sites, namely N234, N165 and N343. We also assessed the effect of a change in the SARS-CoV-2 S glycan shield topology at N370, due to the recently acquired T372A mutation. Our results indicate that the structures of the N-glycans at N234, N165 and N343 affect the stability of the active (or open) S conformation, and thus its exposure and accessibility. Furthermore, while glycosylation at N370 stabilizes the open S conformation, we find that the N370 glycan binds the closed receptor binding domain (RBD) surface, essentially tying the closed protomers together. These results suggest that the loss of the N370 glycosylation site in SARS-CoV-2 may have increased the availability of the open S form, perhaps contributing to its higher infectivity relative to CoV1 and other variants carrying the sequon. Finally, we discuss these specific changes to the topology of the SARS-CoV-2 S glycan shield through ancestral sequence reconstruction of select SARS strains and discuss how they may have evolved to affect S activity.
Keywords	covid19
Language	English
Publishing date	2021-04-01
Publisher	Cold Spring Harbor Laboratory
Document type	Article ; Online
DOI	10.1101/2021.04.01.438036
Database	COVID19

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Article: Beyond Shielding: The Roles of Glycans in the SARS-CoV-2 Spike Protein.

Casalino, Lorenzo / Gaieb, Zied / Goldsmith, Jory A / Hjorth, Christy K / Dommer, Abigail C / Harbison, Aoife M / Fogarty, Carl A / Barros, Emilia P / Taylor, Bryn C / McLellan, Jason S / Fadda, Elisa / Amaro, Rommie E

ACS central science

2020 Volume 6, Issue 10, Page(s) 1722–1734

Abstract: The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively ... ...

Abstract	The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of
Keywords	covid19
Language	English
Publishing date	2020-09-23
Publishing country	United States
Document type	Journal Article
ISSN	2374-7943
ISSN	2374-7943
DOI	10.1021/acscentsci.0c01056
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Beyond Shielding: The Roles of Glycans in SARS-CoV-2 Spike Protein.

bioRxiv : the preprint server for biology

2020

Abstract: The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 15,000,000 infections and 600,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively ... ...

Abstract	The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 15,000,000 infections and 600,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates the host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viruses, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans, and the protein structure and dynamics. We reveal an essential structural role of N-glycans at sites N165 and N234 in modulating the conformational dynamics of the spike's receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift towards the "down" state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of SARS-CoV-2 S protein, which may be exploited by therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.
Keywords	covid19
Language	English
Publishing date	2020-09-04
Publishing country	United States
Document type	Preprint
DOI	10.1101/2020.06.11.146522
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Article ; Online: Beyond Shielding

Lorenzo Casalino / Zied Gaieb / Jory A. Goldsmith / Christy K. Hjorth / Abigail C. Dommer / Aoife M. Harbison / Carl A. Fogarty / Emilia P. Barros / Bryn C. Taylor / Jason S. McLellan / Elisa Fadda / Rommie E. Amaro

ACS Central Science, Vol 6, Iss 10, Pp 1722-

The Roles of Glycans in the SARS-CoV‑2 Spike Protein

2020 Volume 1734

Keywords	Chemistry ; QD1-999
Language	English
Publishing date	2020-09-01T00:00:00Z
Publisher	American Chemical Society
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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