A glycan gate controls opening of the SARS-CoV-2 spike protein

Sztain, Terra; Ahn, Surl-Hee; Bogetti, Anthony T.; Casalino, Lorenzo; Goldsmith, Jory A.; Seitz, E.; McCool, Ryan S.; Kearns, Fiona L.; Acosta-Reyes, F.J.; Maji, Suvrajit; Mashayekhi, Ghoncheh; McCammon, J. Andrew; Ourmazd, A.; Frank, Joachim; McLellan, Jason S.; Chong, Lillian T.; Amaro, Rommie E.

doi:10.1038/s41557-021-00758-3

Cited by 286 publications

(402 citation statements)

References 29 publications

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“…The S protein has a dense coating of glycans, to evade the host immune system. Atomistic simulations also demonstrated that the glycans play an essential role in modulating the conformational transitions of the S protein (18,33,34,49,52). Our models in this study did not include glycans.…”

Section: Discussionmentioning

confidence: 87%

“…New structures of SARS-CoV-2 proteins have been obtained by cryo-electron microscopy (cryo-EM) nearly weekly (16)(17)(18)(19)(20)(21). Computational approaches have also been used for structural prediction of unresolved sections (22), molecular dockings of different drug molecules on virus proteins (23)(24)(25)(26), and free energy calculations of the S-ACE2 binding process (27)(28)(29)(30)(31)(32) and the down-up transition of the receptor binding domain (RBD) (33,34). The larger scale spatio-temporal processes, such as virion assembly, virus architecture, fusion, and budding, are still poorly understood, and remain challenging for experimental techniques as well as all-atom molecular dynamics (MD) simulations (35).…”

Section: Introductionmentioning

confidence: 99%

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The supramolecular organization of SARS-CoV and SARS-CoV-2 virions revealed by coarse-grained models of intact virus envelopes

Wang¹,

Zhong

Tieleman

2021

Preprint

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The coronavirus disease 19 (COVID-19) pandemic is causing a global health crisis and has already caused a devastating societal and economic burden. The pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has a high sequence and architecture identity with SARS-CoV, but far more people have been infected by SARS-CoV-2. Here, combining structural data from cryo-EM and structure prediction, we constructed bottom-up Martini coarse-grained models of intact SARS-CoV and SARS-CoV-2 envelopes. Microsecond molecular dynamics simulations were performed, allowing us to explore their dynamics and supramolecular organization. Both SARS-CoV and SARS-CoV-2 envelopes present a spherical morphology with structural proteins forming multiple string-like islands in the membrane and clusters between heads of spike proteins. Critical differences between the SARS-CoV and SARS-CoV-2 envelopes are the interaction pattern between spike proteins and the flexibility of spike proteins. Our models provide structural and dynamic insights in the SARS virus envelopes, and could be used for further investigation, such as drug design, and fusion and fission processes.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

The supramolecular organization of SARS-CoV and SARS-CoV-2 virions revealed by coarse-grained models of intact virus envelopes

Wang¹,

Zhong

Tieleman

2021

Preprint

View full text Add to dashboard Cite

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“…33 The equilibrium between the “up” and “down” conformations of Spike involves various stabilizing and destabilizing effects, with possible roles for the glycans at N165, N234, N331 and N343 . 22,26,34 Removing the glycans at N165, N234 and N343 was experimentally seen to reduce binding to ACE2 by 10%, 40% and 56%, respectively. 22,26 In our MD simulations, the glycan at position N343 interacts directly with ACE2 (Fig.…”

Section: Resultsmentioning

confidence: 97%

“…22 Furthermore, it has been proposed that the N-glycan at position N343 acts as a gate facilitating RBD opening. 26 Other MD studies concluded that the glycans attached to N90 and N322 of ACE2 could be major determinants of Spike binding, 25 while yet other simulation works postulate that glycosylation does not affect the RBD-ACE2 interaction significantly. 27,28 Genetic or pharmacological blockade of N-glycan biosynthesis at the oligomannose stage in ACE2-expressing target cells was found to dramatically reduce viral entry, 29 even though several glycoforms of ACE2 were found to display comparatively moderate variation with respect to Spike binding.…”

Section: Introductionmentioning

confidence: 99%

Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Capraz

Kienzl

Laurent

et al. 2021

Preprint

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Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients.

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“…This approach was first introduced by Dashti et al 1 and is now termed ManifoldEM 10,11 . Results from previous ManifoldEM studies on biological systems-including the ribosome 1 , ryanodine receptor 10 and SARS-CoV-2 spike protein 12 -have proven its viability and its potential to provide new information on the functional dynamics of molecules.…”

Section: Introductionmentioning

confidence: 99%

Geometric machine learning informed by ground truth: Recovery of conformational continuum from single-particle cryo-EM data of biomolecules

Seitz

Acosta-Reyes

Maji

et al. 2021

Preprint

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This work is based on the manifold-embedding approach to the study of biological molecules exhibiting conformational changes in a continuum. Previous studies established a workflow capable of reconstructing atomic-level structures in the conformational continuum from cryo-EM images so as to reveal the latent space of macromolecules undergoing multiple degrees of freedom. Here, we introduce a new approach that is informed by detailed heuristic analysis of manifolds formed by simulated heterogeneous cryo-EM datasets. These simulated models were generated with increasing complexity to account for multiple motions, state occupancies and CTF in a wide range of signal-to-noise ratios. Using these datasets as ground-truth, we provide detailed exposition of our findings using several conformational motions while exploring the available parameter space. Guided by these insights, we build a framework to leverage the high-dimensional geometric information obtained towards reconstituting the quasi-continuum of conformational states in the form of an energy landscape and respective 3D maps for all states therein. This framework offers substantial enhancements relative to previous work, for which a direct comparison of outputs has been provided.

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A glycan gate controls opening of the SARS-CoV-2 spike protein

Cited by 286 publications

References 29 publications

The supramolecular organization of SARS-CoV and SARS-CoV-2 virions revealed by coarse-grained models of intact virus envelopes

The supramolecular organization of SARS-CoV and SARS-CoV-2 virions revealed by coarse-grained models of intact virus envelopes

Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Geometric machine learning informed by ground truth: Recovery of conformational continuum from single-particle cryo-EM data of biomolecules

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