The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming DOI Creative Commons
Giulia Paiardi, Matheus Ferraz, Marco Rusnati

et al.

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

The accomplices: Heparan sulfates and N-glycans foster SARS-CoV-2 spike:ACE2 receptor binding and virus priming DOI Creative Commons
Giulia Paiardi, Matheus Ferraz, Marco Rusnati

et al.

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

Citations

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