Allosteric Hotspots in the Main Protease of SARS-CoV-2

Strömich, Léonie; Wu, Nan; Barahona, Mauricio; Yaliraki, Sophia N.

doi:10.1016/j.jmb.2022.167748

Cited by 11 publications

(3 citation statements)

References 85 publications

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“…Ohm is a platform for mapping allosteric communication and is based on the perturbation propagation algorithm. It predicts allosteric sites, inter-residue correlations, and communication pathways [54]. A combination of graph theory-based methods like bond-bond propensity analysis and Markov transient analysis have been successfully used to map the allosteric communication pathway in proteins, including the main protease of severe respiratory syndrome coronavirus 2 [55,56].…”

Section: Discussionmentioning

confidence: 99%

“…Duan et al wrote a comprehensive review, which is an excellent read on the advancement of computational methods applied to understand allostery [42]. Thus, various computational strategies have been promising in our journey to understanding allostery in various proteins, including apoptosis related protein, Caspase1 [54], the regulator protein CheY [54], ClpY ATPase [57], Hsp90 [58], monoacylglycerol lipase [19], G protein coupled receptors [59], etc.…”

Section: Discussionmentioning

confidence: 99%

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Mapping allosteric pathway in NIa‐Pro using computational approach

Panigrahi

Kailasam

2023

Quant. Biol.

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Background: Computer simulation studies complement in vitro experiments and provide avenue to understand allosteric regulation in the absence of other molecular viewing techniques. Molecular dynamics captures internal motion within the protein and enables tracing the communication path between a catalytic site and a distal allosteric site. In this article, we have identified the communication pathway between the viral protein genome linked (VPg) binding region and catalytic active site in nuclear inclusion protein-a protease (NIa-Pro). Methods: Molecular dynamics followed by in silico analyses have been used to map the allosteric pathway. Results: This study delineates the residue interaction network involved in allosteric regulation of NIa-Pro activity by VPg. Simulation studies indicate that point mutations in the VPg interaction interface of NIa-Pro lead to disruption in these networks and change the orientation of catalytic residues. His142Ala and His167Ala mutations do not show a substantial change in the overall protease structure, but rather in the residue interaction network and catalytic site geometry. Conclusion: Our mutagenic study delineates the allosteric pathway and facilitates the understanding of the modulation of NIa-Pro activity on a molecular level in the absence of the structure of its complex with the known regulator VPg. Additionally, our in silico analysis explains the molecular concepts and highlights the dynamics behind the previously reported wet lab study findings.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mapping allosteric pathway in NIa‐Pro using computational approach

Panigrahi

Kailasam

2023

Quant. Biol.

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“…Sztain et al, 2020 identified cryptic pocket structures within M pro of SARS-CoV-2 by Gaussian accelerated molecular dynamics, and these pocket structures may serve as drug targets to develop protease inhibitors of COVID-19. Strömich et al, 2022 found by computer simulation that M pro has multiple potentially acting binding sites capable of interfering with viral RNA transcription and protein translation. Günther et al, 2021 identified two metastable binding sites of M pro as possible drug targets a g a i n s t S A R S -C o V -2 b y h i g h -t h r o u g h p u t X -r a y crystallography analysis.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Cao

Gong

et al. 2022

Front. Cell. Infect. Microbiol.

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Purpose2019 Coronavirus disease (COVID-19) is endangering health of populations worldwide. Latest research has proved that Lianhua Qingwen granules (LHQW) can reduce tissue damage caused by inflammatory reactions and relieve patients’ clinical symptoms. However, the mechanism of LHQW treats COVID-19 is currently lacking. Therefore, we employed computer simulations to investigate the mechanism of LHQW treats COVID-19 by modulating inflammatory response.MethodsWe employed bioinformatics to screen active ingredients in LHQW and intersection gene targets. PPI, GO and KEGG was used to analyze relationship of intersection gene targets. Molecular dynamics simulations validated the binding stability of active ingredients and target proteins. Binding free energy, radius of gyration and the solvent accessible surface area were analyzed by supercomputer platform.ResultsCOVID-19 had 4628 gene targets, LHQW had 1409 gene targets, intersection gene targets were 415. Bioinformatics analysis showed that intersection targets were closely related to inflammation and immunomodulatory. Molecular docking suggested that active ingredients (including: licopyranocoumarin, Glycyrol and 3-3-Oxopropanoic acid) in LHQW played a role in treating COVID-19 by acting on CSF2, CXCL8, CCR5, NLRP3, IFNG and TNF. Molecular dynamics was used to prove the binding stability of active ingredients and protein targets.ConclusionThe mechanism of active ingredients in LHQW treats COVID-19 was investigated by computer simulations. We found that active ingredients in LHQW not only reduce cell damage and tissue destruction by inhibiting the inflammatory response through CSF2, CXCL8, CCR5 and IFNG, but also regulate cell survival and growth through NLRP3 and TNF thereby reducing apoptosis.

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Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application

Raza,

Zhong,

et al. 2023

Mol Biotechnol

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Allosteric Hotspots in the Main Protease of SARS-CoV-2

Cited by 11 publications

References 85 publications

Mapping allosteric pathway in NIa‐Pro using computational approach

Mapping allosteric pathway in NIa‐Pro using computational approach

Molecular docking and molecular dynamics study Lianhua Qingwen granules (LHQW) treats COVID-19 by inhibiting inflammatory response and regulating cell survival

Advances of Predicting Allosteric Mechanisms Through Protein Contact in New Technologies and Their Application

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