Conformational Behavior of SARS-Cov-2 Spike Protein Variants: Evolutionary Jumps in Sequence Reverberate in Structural Dynamic Differences

Triveri, Alice; Casali, Emanuele; Frasnetti, Elena; Doria, Filippo; Frigerio, Francesco; Cinquini, Fabrizio; Pavoni, Silvia; Moroni, Elisabetta; Marchetti, Filippo; Serapian, Stefano A.; Colombo, Giorgio

doi:10.1021/acs.jctc.3c00077

Cited by 4 publications

(1 citation statement)

References 74 publications

(161 reference statements)

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“…They found that epitope exposure, measured by accessible surface area, was observed to remain constant or increase significantly during the transition from the ‘down’ to the ‘up’ state of RBD, impacting the binding of some but not all of the evaluated antibodies. Other studies used explicit dynamic information on wild-type SARS-CoV-2 S protein and several mutants to reveal the intrinsic determinants of epitope presentation and the mechanisms of antibody escape [ 153 , 154 , 155 ]; in all of these cases, mutations modify the glycan-shield of the S protein with a strong impact on its dynamics and recognition properties.…”

Section: Therapeutic Implications—targeting Conformational and Assemb...mentioning

confidence: 99%

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

Pasala,

Sharma,

Roychowdhury

et al. 2024

Biomolecules

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Glycosylation, a prevalent post-translational modification, plays a pivotal role in regulating intricate cellular processes by covalently attaching glycans to macromolecules. Dysregulated glycosylation is linked to a spectrum of diseases, encompassing cancer, neurodegenerative disorders, congenital disorders, infections, and inflammation. This review delves into the intricate interplay between glycosylation and protein conformation, with a specific focus on the profound impact of N-glycans on the selection of distinct protein conformations characterized by distinct interactomes—namely, protein assemblies—under normal and pathological conditions across various diseases. We begin by examining the spike protein of the SARS virus, illustrating how N-glycans regulate the infectivity of pathogenic agents. Subsequently, we utilize the prion protein and the chaperone glucose-regulated protein 94 as examples, exploring instances where N-glycosylation transforms physiological protein structures into disease-associated forms. Unraveling these connections provides valuable insights into potential therapeutic avenues and a deeper comprehension of the molecular intricacies that underlie disease conditions. This exploration of glycosylation’s influence on protein conformation effectively bridges the gap between the glycome and disease, offering a comprehensive perspective on the therapeutic implications of targeting conformational mutants and their pathologic assemblies in various diseases. The goal is to unravel the nuances of these post-translational modifications, shedding light on how they contribute to the intricate interplay between protein conformation, assembly, and disease.

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Section: Therapeutic Implications—targeting Conformational and Assemb...mentioning

confidence: 99%

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

Pasala,

Sharma,

Roychowdhury

et al. 2024

Biomolecules

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Design and Test of Molecules that Interfere with the Recognition Mechanisms between the SARS-CoV-2 Spike Protein and Its Host Cell Receptors

Scantamburlo,

Masgras,

Ciscato

et al. 2024

J. Chem. Inf. Model.

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The disruptive impact of the COVID-19 pandemic has led the scientific community to undertake an unprecedented effort to characterize viral infection mechanisms. Among these, interactions between the viral glycosylated Spike and the human receptors ACE2 and TMPRSS2 are key to allowing virus invasion. Here, we report and test a fully rational methodology to design molecules that are capable of perturbing the interactions between these critical players in SARS-CoV-2 pathogenicity. To this end, we computationally identify substructures on the fully glycosylated Spike protein that are not intramolecularly optimized and are thus prone to being stabilized by forming complexes with ACE2 and TMPRSS2. With the aim of competing with the Spike-mediated cell entry mechanisms, we have engineered the predicted putative interaction regions in the form of peptide mimics that could compete with Spike for interaction with ACE2 and/or TMPRSS2. Experimental models of viral entry demonstrate that the designed molecules are able to interfere with viral entry into ACE2/TMPRSS2 expressing cells, while they have no effects on the entry of control viral particles that do not harbor the Spike protein or on the entry of Spike-presenting viral particles into cells that do not display its receptors on their surface.

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In silico identification of five binding sites on the SARS-CoV-2 spike protein and selection of seven ligands for such sites

de Oliveira

2023

Journal of Biomolecular Structure and Dynamics

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Conformational Behavior of SARS-Cov-2 Spike Protein Variants: Evolutionary Jumps in Sequence Reverberate in Structural Dynamic Differences

Cited by 4 publications

References 74 publications

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

N-Glycosylation as a Modulator of Protein Conformation and Assembly in Disease

Design and Test of Molecules that Interfere with the Recognition Mechanisms between the SARS-CoV-2 Spike Protein and Its Host Cell Receptors

In silico identification of five binding sites on the SARS-CoV-2 spike protein and selection of seven ligands for such sites

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