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

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(43)

Опубликована: Окт. 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.

Язык: Английский

Quantitative Prediction of Protein–Polyelectrolyte Binding Thermodynamics: Adsorption of Heparin-Analog Polysulfates to the SARS-CoV-2 Spike Protein RBD DOI Creative Commons

Lenard Neander,

Cedric Hannemann,

Roland R. Netz

и другие.

JACS Au, Год журнала: 2025, Номер unknown

Опубликована: Янв. 6, 2025

Interactions of polyelectrolytes (PEs) with proteins play a crucial role in numerous biological processes, such as the internalization virus particles into host cells. Although docking, machine learning methods, and molecular dynamics (MD) simulations are utilized to estimate binding poses free energies small-molecule drugs proteins, quantitative prediction thermodynamics PE-based presents significant obstacle computer-aided drug design. This is due sluggish PEs caused by their size strong charge-charge correlations. In this paper, we introduce advanced sampling methods based on force-spectroscopy setup theoretical modeling overcome barrier. We exemplify our method explicit solvent all-atom MD interactions between anionic that show antiviral properties, namely heparin linear polyglycerol sulfate (LPGS), SARS-CoV-2 spike protein receptor domain (RBD). Our for free-energy LPGS wild-type RBD matches experimentally measured dissociation constants within thermal energy, k B T, correctly reproduces experimental PE-length dependence. find binds Delta-variant an additional gain 2.4 compared RBD, presence two mutated cationic residues contributing electrostatic energy gain. LPGS-RBD dominated enthalpy driven, though large entropy-enthalpy compensation. applicable general polymer adsorption phenomena predicts precise reconfigurational friction needed drug-delivery

Язык: Английский

Процитировано

0
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

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2024, Номер 121(43)

Опубликована: Окт. 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.

Язык: Английский

Процитировано

2