Many Roles of Carbohydrates: A Computational Spotlight on the Coronavirus S Protein Binding

Maity, Suman Kalyan; Acharya, Atanu

doi:10.1021/acsabm.2c01064

Cited by 7 publications

(4 citation statements)

References 135 publications

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“…The spike trimer has been discovered to contain numerous glycosylation sites, with ~40% of the protein being shielded by glycans 97 . Since cryo‐EM and x‐ray crystallography are unable to accurately determine glycan composition, computational simulation has emerged as a vital tool for studying the glycosylation of spike protein 98,99 . Glycans impact the spike/ACE2 binding in three primary ways: first, they influence the down‐to‐up dynamics of spike conformation 32,100 ; second, they alter glycan‐protein or glycan–glycan interactions 101,102 ; and third, they modify the interface by either shielding binding sites or displacing the binding residues 103,104 .…”

Section: Discussionmentioning

confidence: 99%

Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

An,

Yang,

Luo

et al. 2024

Proteins

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The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) characterized by 30 mutations in its spike protein, has rapidly spread worldwide since November 2021, significantly exacerbating the ongoing COVID‐19 pandemic. In order to investigate the relationship between these mutations and the variant's high transmissibility, we conducted a systematic analysis of the mutational effect on spike–angiotensin‐converting enzyme‐2 (ACE2) interactions and explored the structural/energy correlation of key mutations, utilizing a reliable coarse‐grained model. Our study extended beyond the receptor‐binding domain (RBD) of spike trimer through comprehensive modeling of the full‐length spike trimer rather than just the RBD. Our free‐energy calculation revealed that the enhanced binding affinity between the spike protein and the ACE2 receptor is correlated with the increased structural stability of the isolated spike protein, thus explaining the omicron variant's heightened transmissibility. The conclusion was supported by our experimental analyses involving the expression and purification of the full‐length spike trimer. Furthermore, the energy decomposition analysis established those electrostatic interactions make major contributions to this effect. We categorized the mutations into four groups and established an analytical framework that can be employed in studying future mutations. Additionally, our calculations rationalized the reduced affinity of the omicron variant towards most available therapeutic neutralizing antibodies, when compared with the wild type. By providing concrete experimental data and offering a solid explanation, this study contributes to a better understanding of the relationship between theories and observations and lays the foundation for future investigations.

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Section: Discussionmentioning

confidence: 99%

Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

An,

Yang,

Luo

et al. 2024

Proteins

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“…Since its emergence, SARS-CoV-2 has undergone continuous mutations and recent evidence shows that some variants of concern like Delta or Omicron display differences in N-glycan processing (Zheng et al, 2022;Baboo et al, 2023) which may affect the infectivity like shown for the Omicron BA.1 variant (Lusvarghi et al, 2023). These findings underscore the importance of N-glycosylation for SARS-CoV-2 virus infection (Gong et al, 2021;Maity and Acharya, 2023) and the requirement for platforms and expression systems that allow the production of defined homogenous glycan structures on recombinant viral proteins (Yang et al, 2015;Schwestka et al, 2021;Hsu et al, 2023). Since even small differences in glycosylation may alter the immune response (Samuelsson et al, 2022), a controlled glycosylation profile on protein subunit vaccines is highly desirable.…”

Section: Introductionmentioning

confidence: 94%

Impact of mutations on the plant-based production of recombinant SARS-CoV-2 RBDs

Ruocco,

Vavra,

König-Beihammer

et al. 2023

Front. Plant Sci.

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Subunit vaccines based on recombinant viral antigens are valuable interventions to fight existing and evolving viruses and can be produced at large-scale in plant-based expression systems. The recombinant viral antigens are often derived from glycosylated envelope proteins of the virus and glycosylation plays an important role for the immunogenicity by shielding protein epitopes. The receptor-binding domain (RBD) of the SARS-CoV-2 spike is a principal target for vaccine development and has been produced in plants, but the yields of recombinant RBD variants were low and the role of the N-glycosylation in RBD from different SARS-CoV-2 variants of concern is less studied. Here, we investigated the expression and glycosylation of six different RBD variants transiently expressed in leaves of Nicotiana benthamiana. All of the purified RBD variants were functional in terms of receptor binding and displayed almost full N-glycan occupancy at both glycosylation sites with predominately complex N-glycans. Despite the high structural sequence conservation of the RBD variants, we detected a variation in yield which can be attributed to lower expression and differences in unintentional proteolytic processing of the C-terminal polyhistidine tag used for purification. Glycoengineering towards a human-type complex N-glycan profile with core α1,6-fucose, showed that the reactivity of the neutralizing antibody S309 differs depending on the N-glycan profile and the RBD variant.

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“…These glycans can shield antigenic sites from immune surveillance, affecting viral neutralization and immune evasion strategies ( 19-22 ). Previous studies have also demonstrated that the glycans play other roles beyond shielding the S protein from host immune recognition ( 23, 24 ). Since the outbreak of the COVID-19 pandemic, the glycosylation profile of the SARS-CoV-2 S glycoproteins on the initial strain and evolving variants has been intensively studied, particularly through the use of advanced liquid chromatography coupled to tandem mass spectrometry (LC-MS) techniques ( 20, 23, 25-41 ) with recombinantly expressed proteins of ectodomain or subunit constructs and even viral derived S protein ( 14 ).…”

Section: Introductionmentioning

confidence: 99%

Enhanced surface accessibility of SARS-CoV-2 Omicron spike protein due to an altered glycosylation profile

Wang,

Zhang,

Baudys

et al. 2023

Preprint

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SARS-CoV-2 spike (S) proteins undergo extensive glycosylation, aiding proper folding, enhancing stability, and evading host immune surveillance. In this study, we used mass spectrometric analysis to elucidate the N-glycosylation characteristics and disulfide bonding of recombinant spike proteins derived from the SARS-CoV-2 Omicron variant (B.1.1.529) in comparison with the D614G spike variant. Furthermore, we conducted microsecond-long molecular dynamics simulations on spike proteins to resolve how the different N-glycans impact spike conformational sampling in the two variants. Our findings reveal that the Omicron spike protein maintains an overall resemblance to the D614G spike variant in terms of site-specific glycan processing and disulfide bond formation. Nonetheless, alterations in glycans were observed at certain N-glycosylation sites. These changes, in synergy with mutations within the Omicron spike protein, result in increased surface accessibility of the macromolecule, including ectodomain, receptor-binding domain, and N-terminal domain. These insights contribute to our understanding of the interplay between structure and function, thereby advancing effective vaccination and therapeutic strategies.TeaserThrough mass spectrometry and molecular dynamics simulations, SARS-CoV-2 Omicron spike is found to be less covered by glycans when compared to the D614G spike variant.

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Many Roles of Carbohydrates: A Computational Spotlight on the Coronavirus S Protein Binding

Cited by 7 publications

References 135 publications

Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

Mechanistic study of the transmission pattern of the SARS‐CoV‐2 omicron variant

Impact of mutations on the plant-based production of recombinant SARS-CoV-2 RBDs

Enhanced surface accessibility of SARS-CoV-2 Omicron spike protein due to an altered glycosylation profile

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