Role of N343 glycosylation on the SARS-CoV-2 S RBD structure and co-receptor binding across variants of concern

eLife, Journal Year: 2024, Volume and Issue: 13

Published: March 27, 2024

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

Language: Английский

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SARS-CoV-2 spike protein in infectivity

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 21 - 56

Published: Jan. 1, 2025

Language: Английский

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Subtle Changes at the RBD/hACE2 Interface During SARS-CoV-2 Variant Evolution: A Molecular Dynamics Study

Biomolecules, Journal Year: 2025, Volume and Issue: 15(4), P. 541 - 541

Published: April 7, 2025

The SARS-CoV-2 Omicron variants show different behavior compared to the previous variants, especially with respect Delta variant, which promotes a lower morbidity despite being much more contagious. In this perspective, we performed molecular dynamics (MD) simulations of spike RBD/hACE2 complexes corresponding WT, and four variants. Carrying out comprehensive analysis residue interactions within between two partners allowed us draw profile each variant by using complementary methods (PairInt, hydrophobic potential, contact PCA). PairInt calculations highlighted residues most involved in electrostatic interactions, make strong contribution binding highly stable RBD hACE2. Apolar contacts made substantial detection patches. Contact networks cross-correlation matrices were able detect subtle changes at point mutations as S375F mutation occurring all is likely confer an advantage stability. This study brings new highlights on dynamic hACE2, may explain final persistence over Delta.

Language: Английский

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The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(43)

Published: Oct. 14, 2024

Although it is well established that the SARS-CoV-2 spike glycoprotein binds to host cell ACE2 receptor initiate infection, far less known about tissue tropism and susceptibility virus. Differential expression across different types of heparan sulfate (HS) proteoglycans, with variably sulfated glycosaminoglycans (GAGs), their synergistic interactions viral N-glycans may contribute susceptibility. Nevertheless, contribution remains unclear since HS evade experimental characterization. We, therefore, carried out microsecond-long all-atom molecular dynamics simulations, followed by random acceleration fully glycosylated spike:ACE2 complex without highly GAG chains bound. By considering model GAGs as surrogates for expressed in lung cells, we identified key entry mechanisms SARS-CoV-2. We find promotes structural energetic stabilization active conformation receptor-binding domain (RBD) reorientation toward N-terminal same subunit RBD. Spike exert effects, promoting better packing, strengthening protein:protein interaction, prolonging residence time complex. binding trigger rearrangement S2’ functional protease cleavage site through allosteric interdomain communication. These results thus show has a multifaceted role facilitating they provide mechanistic basis development derivatives anti-SARS-CoV-2 potential.

Language: Английский

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

ACS Applied Bio Materials, Journal Year: 2023, Volume and Issue: 7(2), P. 646 - 656

Published: March 22, 2023

Glycosylation is one of the post-translational modifications with more than 50% human proteins being glycosylated. The exact nature and chemical composition glycans are inaccessible to X-ray or cryo-electron microscopy imaging techniques. Therefore, computational modeling studies molecular dynamics must be used as a "computational microscope". spike (S) protein SARS-CoV-2 heavily glycosylated, few play functional role "beyond shielding". In this mini-review, we discuss investigations roles specific S-protein ACE2 in overall ACE2-S binding. We highlight different functions demonstrated myriad models simulations context virus binding receptor. also interactions between glycocalyx S protein, which may utilized design prophylactic polysaccharide-based therapeutics targeting protein. addition, underline recent emergence coronavirus variants their impact on its glycans.

Language: Английский

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Can ChatGPT pass Glycobiology?

Glycobiology, Journal Year: 2023, Volume and Issue: 33(8), P. 606 - 614

Published: Aug. 1, 2023

The release of text-generating applications based on interactive Large Language Models (LLMs) in late 2022 triggered an unprecedented and ever-growing interest worldwide. almost instantaneous success LLMs stimulated lively discussions public media academic fora alike not only the value potentials such tools all areas knowledge information acquisition distribution but also dangers posed by their uncontrolled indiscriminate use. This conversation is now particularly active higher education sector, where are seen as a potential threat to integrity at levels, from facilitating cheating students assignments plagiarizing writing case researchers administrators. Within this framework, we interested testing boundaries LLM ChatGPT (www.openai.com) our scientific expertise analyzing results different perspectives, i.e. final year BSc student, research scientist, lecturer education. To end, paper, present discuss systematic evaluation how addresses progressively complex tasks exam-type questions Carbohydrate Chemistry Glycobiology. project allowed us gain insight on: (i) strengths limitations model provide relevant (most importantly) correct information, (ii) format(s) complexity query required obtain desired output, (iii) strategies integrate teaching learning.

Language: Английский

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Mechanisms of allostery at the viral surface through the eyes of molecular simulation

Current Opinion in Structural Biology, Journal Year: 2023, Volume and Issue: 84, P. 102761 - 102761

Published: Dec. 23, 2023

Language: Английский

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Stabilization of the Metastable Pre-Fusion Conformation of the SARS-CoV-2 Spike Glycoprotein through N-Linked Glycosylation of the S2 Subunit

Viruses, Journal Year: 2024, Volume and Issue: 16(2), P. 223 - 223

Published: Jan. 31, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the novel responsible for disease 2019 (COVID-19) pandemic, represents a serious threat to public health. The spike (S) glycoprotein of SARS-CoV-2 mediates viral entry into host cells and is heavily glycosylated. In this study, we systemically analyzed roles 22 putative N-linked glycans in S protein expression, membrane fusion, entry, stability. Using α-glycosidase inhibitors castanospermine NB-DNJ, confirmed that disruption glycosylation blocked maturation protein, leading impairment protein-mediated fusion. Single-amino-acid substitution each sites with glutamine revealed 9 out were critical folding maturation. Thus, at these resulted reduced cell–cell fusion entry. Notably, N1074Q mutation markedly affected stability induced significant receptor-independent syncytium (RIS) formation HEK293T/hACE2-KO cells. Additionally, removal furin cleavage site partially compensated instability by mutation. Although corresponding SARS-CoV (N1056Q) did not induce RIS HEK293T cells, N669Q N1080Q mutants exhibited increased fusogenic activity Therefore, N-glycans on S2 subunits are highly important maintaining pre-fusion state protein. This study stability, information has implications design vaccines antiviral strategies.

Language: Английский

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Deep learning-based automatic segmentation of COVID-19 in chest X-ray images using ensemble neural net sentinel algorithm

Measurement Sensors, Journal Year: 2024, Volume and Issue: 33, P. 101117 - 101117

Published: March 26, 2024

COVID-19 has affected billions of people worldwide and serious public health effects. Automatic image segmentation is crucial to improve clinical decision-making for full assessments illness management as well monitoring. It plays a part in detecting, diagnosing, tracking diseases by allowing the exact or accurate diseased regions. classifying medical images remains most difficult obstacle diagnosis, however, because lack annotated images. In this article, we propose Ensemble Neural Net Sentinel Algorithm (ENNSA), unique deep learning (DL) method classification COVID-19. Chest X-ray dataset first collected from Kaggle preprocessed. The features processed are retrieved using Insistent Grey Level Co-occurrence Matrix (IGLCM). suggested ENNSA outperforms current techniques terms accuracy (99.25), precision (100), recall (43), F1 score (61) regardless unbalanced datasets, indicating its promise diagnostic tool respiratory diseases. addition, approach used separate chosen chest investigational outcomes demonstrate that our proposed strategy currently methods

Language: Английский

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Enhanced Surface Accessibility of SARS-CoV-2 Omicron Spike Protein Due to an Altered Glycosylation Profile

ACS Infectious Diseases, Journal Year: 2024, Volume and Issue: 10(6), P. 2032 - 2046

Published: May 10, 2024

SARS-CoV-2 spike (S) proteins undergo extensive glycosylation, aiding in proper folding, enhancing stability, and evading host immune surveillance. In this study, we used mass spectrometric analysis to elucidate the N-glycosylation characteristics disulfide bonding of recombinant derived from Omicron variant (B.1.1.529) comparison with D614G variant. Furthermore, conducted microsecond-long molecular dynamics simulations on resolve how different N-glycans impact conformational sampling two variants. Our findings reveal that protein maintains an overall resemblance terms site-specific glycan processing bond formation. Nonetheless, alterations glycans were observed at certain sites. These changes, synergy mutations within protein, result increased surface accessibility macromolecule, including ectodomain, receptor-binding domain, N-terminal domain. Additionally, mutagenesis pull-down assays role glycosylation a specific sequon (N149); furthermore, correlation MD simulation HDX-MS identified several high-dynamic areas proteins. insights contribute our understanding interplay between structure function, thereby advancing effective vaccination therapeutic strategies.

Language: Английский

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