SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

Pang, Yui Tik; Acharya, Atanu; Lynch, Diane L.; Pavlova, Ànna; Gumbart, James C.

doi:10.1038/s42003-022-04138-6

Cited by 50 publications

(97 citation statements)

References 84 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Structural analysis revealed that the RBD could possess up and down configurations, in which an up-conformation favors the interaction with ACE2 or ACE2-blocking neutralization antibodies [ 32 , 41 , 48 , 49 , 50 , 51 ], while the RBD in down-conformation masks ACE2-interacting interfaces and hides potential antigenic epitopes [ 52 ] ( Figure 2 B). The configurations of the RBD can be additionally regulated by glycans, fatty acids, and physical temperature [ 52 , 53 , 54 ], or individual mutations within the S1 subunits, such as amino acid substitution at the D614G [ 55 , 56 ] or altered hydrophobicity at S375F [ 57 ]. Nevertheless, the S1 subunit senses the entry signal derived from target cell receptor binding and translates it into the activating signal for the S2 subunit.…”

Section: The Sars-cov-2 Spikementioning

confidence: 99%

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

et al. 2023

Viruses

View full text Add to dashboard Cite

The constantly evolving severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOC) fuel the worldwide coronavirus disease (COVID-19) pandemic. The spike protein is essential for the SARS-CoV-2 viral entry and thus has been extensively targeted by therapeutic antibodies. However, mutations along the spike in SARS-CoV-2 VOC and Omicron subvariants have caused more rapid spread and strong antigenic drifts, rendering most of the current antibodies ineffective. Hence, understanding and targeting the molecular mechanism of spike activation is of great interest in curbing the spread and development of new therapeutic approaches. In this review, we summarize the conserved features of spike-mediated viral entry in various SARS-CoV-2 VOC and highlight the converging proteolytic processes involved in priming and activating the spike. We also summarize the roles of innate immune factors in preventing spike-driven membrane fusion and provide outlines for the identification of novel therapeutics against coronavirus infections.

show abstract

Section: The Sars-cov-2 Spikementioning

confidence: 99%

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

et al. 2023

Viruses

View full text Add to dashboard Cite

show abstract

“… 9 , 38 The glycans represent ∼25% of the mass 9 and cover ∼40% of the surface area 12 of the SARS-CoV-2 S protein. Collectively, these glycans create a protective shield on the spike protein to avoid detection by the immune system 10 , 11 , 15 ( Figure 2 A). However, an average representation of the covered surface area may not be conclusive evidence of glycans’ shielding effect since some can be removed from their binding site by the antibody.…”

Section: Impact Of S-protein Glycansmentioning

confidence: 99%

“…(B) S-protein glycans at N165, N234, and N343 play intricate roles in stabilizing the down and the up state. The top and bottom panels are reproduced with permission from ref ( 10 ) (Copyright 2020 American Chemical Society) and ref ( 15 ) (Copyright 2022 Gumbart and co-workers), respectively.…”

Section: Impact Of S-protein Glycansmentioning

confidence: 99%

“… 15 , 32 The minimum energy path (MEP) along a 2-D potential of mean force (PMF) calculated using replica-exchange umbrella sampling (REUS) reveals that the glycans at N165 and N122 disrupt the hydrogen bonds between the open RBD and the NTD of the adjacent protomer. 15 The glycan at N343 shields the RBD surface in the down state. 32 It also opens with RBD and lifts the RBD through multiple sequential glycan–protein interactions, creating the so-called “ glycan-gating ” effect.…”

Section: Impact Of S-protein Glycansmentioning

confidence: 99%

See 1 more Smart Citation

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

Maity

Acharya

2023

ACS Appl. Bio Mater.

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…Computer simulations provided important atomistic and mechanistic advances into understanding the dynamics and function of the SARS-CoV-2 S proteins. All-atom molecular dynamics (MD) simulations of the full-length SARS-CoV-2 S glycoprotein embedded in the viral membrane, with a complete glycosylation profile provided detailed characterization of the conformational landscapes of the S proteins in the physiological environment [56][57][58][59][60][61]. Using distributed cloudbased computing, large scale MD simulations of the viral proteome observed dramatic opening of the S protein complex, predicting the existence of several cryptic epitopes in the S protein [62].…”

mentioning

confidence: 99%

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

Verkhivker

Alshahrani

Gupta

2023

Preprint

View full text Add to dashboard Cite

The evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity, conformational plasticity, protein stability and allosteric modulation. In this study, we embarked on a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability and allostery in the different functional states of spike trimers for BA.1, BA.2, and BA.2.75 variants. Using efficient and accurate coarse-grained simulations and atomistic reconstruction of the ensembles, we examined conformational dynamics of the spike trimers that agrees with the recent functional studies, suggesting that BA.2.75 trimers are the most stable among these variants. A systematic mutational scanning of the inter-protomer interfaces in the spike trimers revealed a group of conserved structural stability hotspots that play a key role in modulation of functional dynamics and are also involved in the inter-protomer couplings through local contacts and interaction networks with the Omicron mutational sites. The results of mutational scanning provided evidence that BA.2.75 trimers are more stable than BA.2 and comparable in stability to BA.1 variant. Using dynamic network modeling of the S Omicron BA.1, BA.2 and BA.2.75 trimers we showed that the key network positions driving long-range signaling are associated with the major stability hotspots that are inter-connected along potential communication pathways, while sites of Omicron mutations may often correspond to weak spots of stability and allostery but are coupled to the major stability hotspots through interaction networks. The presented analysis of the BA.1, BA.2 and BA.2.75 trimers suggested that thermodynamic stability of BA.1 and BA.2.75 variants may be intimately linked with the residue interaction network organization that allows for a broad ensemble of allosteric communications in which signaling between structural stability hotspots may be modulated by the Omicron mutational sites. The findings provided plausible rationale for mechanisms in which Omicron mutations can evolve to balance thermodynamic stability and conformational adaptability in order to ensure proper tradeoff between stability, binding and immune escape.

show abstract

SARS-CoV-2 spike opening dynamics and energetics reveal the individual roles of glycans and their collective impact

Cited by 50 publications

References 84 publications

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

SARS-CoV-2 Spike-Mediated Entry and Its Regulation by Host Innate Immunity

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

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers : Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

Contact Info

Product

Resources

About