Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins.
J Proteome Res
; 19(11): 4587-4608, 2020 11 06.
Article
in English
| MEDLINE | ID: covidwho-811635
ABSTRACT
The development of computational strategies for the quantitative characterization of the functional mechanisms of SARS-CoV-2 spike proteins is of paramount importance in efforts to accelerate the discovery of novel therapeutic agents and vaccines combating the COVID-19 pandemic. Structural and biophysical studies have recently characterized the conformational landscapes of the SARS-CoV-2 spike glycoproteins in the prefusion form, revealing a spectrum of stable and more dynamic states. By employing molecular simulations and network modeling approaches, this study systematically examined functional dynamics and identified the regulatory centers of allosteric interactions for distinct functional states of the wild-type and mutant variants of the SARS-CoV-2 prefusion spike trimer. This study presents evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states. Perturbation-based modeling of the interaction networks revealed a key role of the cross-talk between the effector hotspots in the receptor binding domain and the fusion peptide proximal region of the SARS-CoV-2 spike protein. The results have shown that the allosteric hotspots of the interaction networks in the SARS-CoV-2 spike protein can control the dynamic switching between functional conformational states that are associated with virus entry to the host receptor. This study offers a useful and novel perspective on the underlying mechanisms of the SARS-CoV-2 spike protein through the lens of allosteric signaling as a regulatory apparatus of virus transmission that could open up opportunities for targeted allosteric drug discovery against SARS-CoV-2 proteins and contribute to the rapid response to the current and potential future pandemic scenarios.
Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Pneumonia, Viral
/
Coronavirus Infections
/
Allosteric Regulation
/
Molecular Dynamics Simulation
/
Spike Glycoprotein, Coronavirus
/
Betacoronavirus
Type of study:
Randomized controlled trials
Topics:
Vaccines
/
Variants
Limits:
Humans
Language:
English
Journal:
J Proteome Res
Journal subject:
Biochemistry
Year:
2020
Document Type:
Article
Affiliation country:
Acs.jproteome.0c00654
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