Probing the formation, structure and free energy relationships of M protein dimers of SARS-CoV-2

Cao, Yipeng; Wang, Wei; Jiang, Shengpeng; Yang, Chengwen; Liu, Ningbo; Dai, Hongji; Lee, Imshik; Meng, Xiangyi

doi:10.1016/j.csbj.2022.01.007

Cited by 14 publications

(12 citation statements)

References 63 publications

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“…Feig’s laboratory has also proposed two possible configuration arrangements for the M protein homodimer [ 70 ], which were named by Monje-Galvan et al as “open” and “closed” conformations [ 69 ]. The dimer structure configuration obtained in our study is similar to the “open” one ( Supplementary Figure S14 ), and it is also supported by other authors, such as Cao et al [ 27 ]. Monje-Galvan et al [ 69 ] also described the interface region of the homodimer in the TMH2 and TMH3 regions [ 69 ], which also comes into agreement with our study.…”

Section: Discussionsupporting

confidence: 91%

“…M protein is constituted by 223 amino acids and has three major domains: a short- N-terminal ecto-domain, three TransMembrane Helices (labelled as TMH1, TMH2, and TMH3), and a long C-terminal endo-domain located on the cytoplasmic face of virions [ 12 , 13 , 19 , 26 ]. There are few reports of M protein homodimers, but those that exist explain only in part the process of homodimer formation through M–M interactions [ 9 , 12 , 13 , 14 , 15 , 27 ]. M protein molecules interact with each other through multiple contact sites, especially in transmembrane domains [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

Marques-Pereira

Pires

Gouveia

et al. 2022

IJMS

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Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV-2) is composed of four structural proteins and several accessory non-structural proteins. SARS-CoV-2’s most abundant structural protein, Membrane (M) protein, has a pivotal role both during viral infection cycle and host interferon antagonism. This is a highly conserved viral protein, thus an interesting and suitable target for drug discovery. In this paper, we explain the structural nature of M protein homodimer. To do so, we developed and applied a detailed and robust in silico workflow to predict M protein dimeric structure, membrane orientation, and interface characterization. Single Nucleotide Polymorphisms (SNPs) in M protein were retrieved from over 1.2 M SARS-CoV-2 genomes and proteins from the Global Initiative on Sharing All Influenza Data (GISAID) database, 91 of which were located at the predicted dimer interface. Among those, we identified SNPs in Variants of Concern (VOC) and Variants of Interest (VOI). Binding free energy differences were evaluated for dimer interfacial SNPs to infer mutant protein stabilities. A few high-prevalent mutated residues were found to be especially relevant in VOC and VOI. This realization may be a game-changer to structure-driven formulation of new therapeutics for SARS-CoV-2.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

Marques-Pereira

Pires

Gouveia

et al. 2022

IJMS

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“…We propose W20, with an ASA of 157 Å 2 , and G126, which is highly accessible but with an ASA of 72.96 Å 2 as it is a smaller amino acid, are likely important in virion assembly interactions and could be targeted by small molecule inhibitors. W20 is within a transmembrane domain and may be involved in M dimerization [ 70 ]. Small-molecule and anti-TMD peptides can inhibit interactions within membranes [ 71 ], and this approach to inhibit M dimerization would block virion assembly.…”

Section: Resultsmentioning

confidence: 99%

“…Small-molecule and anti-TMD peptides can inhibit interactions within membranes [ 71 ], and this approach to inhibit M dimerization would block virion assembly. G126 is within the C-terminal domain (CTD) of M, a flexible region of the protein [ 70 ] that we speculate could serve to interact with other proteins during the viral life cycle.…”

Section: Resultsmentioning

confidence: 99%

Conserved Targets to Prevent Emerging Coronaviruses

Lomeli

Elmaraghy

Castro

et al. 2022

Viruses

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Novel coronaviruses emerged as zoonotic outbreaks in humans in 2003 (SARS), 2012 (MERS), and notably in 2019 (SARS2), which resulted in the COVID-19 pandemic, causing worldwide health and economic disaster. Vaccines provide the best protection against disease but cannot be developed and engineered quickly enough to prevent emerging viruses, zoonotic outbreaks, and pandemics. Antivirals are the best first line of therapeutic defense against novel emerging viruses. Coronaviruses are plus sense, single stranded, RNA genome viruses that undergo frequent genetic mutation and recombination, allowing for the emergence of novel coronavirus strains and variants. The molecular life cycle of the coronavirus family offers many conserved activities to be exploited as targets for antivirals. Here, we review the molecular life cycle of coronaviruses and consider antiviral therapies, approved and under development, that target the conserved activities of coronaviruses. To identify additional targets to inhibit emerging coronaviruses, we carried out in silico sequence and structure analysis of coronavirus proteins isolated from bat and human hosts. We highlight conserved and accessible viral protein domains and residues as possible targets for the development of viral inhibitors. Devising multiple antiviral therapies that target conserved viral features to be used in combination is the best first line of therapeutic defense to prevent emerging viruses from developing into outbreaks and pandemics.

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“…The most abundant M protein is responsible for sorting and the incorporation of viral components in the budding virions and maintaining the shape and size of CoVs [4,7,14]. The M protein (about 230 amino acids) has three transmembrane domains and usually exists in the form of functional dimers [14,15]. It forms the matrix of the envelope and interacts with all other structural proteins.…”

Section: Introductionmentioning

confidence: 99%

Electrostatic Map of the SARS-CoV-2 Virion Specifies Binding Sites of the Antiviral Cationic Photosensitizer

Fedorov

Kholina

Khruschev

et al. 2022

IJMS

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Electrostatics is an important part of virus life. Understanding the detailed distribution of charges over the surface of a virus is important to predict its interactions with host cells, antibodies, drugs, and different materials. Using a coarse-grained model of the entire viral envelope developed by D. Korkin and S.-J. Marrink’s scientific groups, we created an electrostatic map of the external surface of SARS-CoV-2 and found a highly heterogeneous distribution of the electrostatic potential field of the viral envelope. Numerous negative patches originate mainly from negatively charged lipid domains in the viral membrane and negatively charged areas on the “stalks” of the spike (S) proteins. Membrane (M) and envelope (E) proteins with the total positive charge tend to colocalize with the negatively charged lipids. In the E protein pentamer exposed to the outer surface, negatively charged glutamate residues and surrounding lipids form a negative electrostatic potential ring around the channel entrance. We simulated the interaction of the antiviral octacationic photosensitizer octakis(cholinyl)zinc phthalocyanine with the surface structures of the entire model virion using the Brownian dynamics computational method implemented in ProKSim software (version r661). All mentioned negatively charged envelope components attracted the photosensitizer molecules and are thus potential targets for reactive oxygen generated in photosensitized reactions.

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Probing the formation, structure and free energy relationships of M protein dimers of SARS-CoV-2

Cited by 14 publications

References 63 publications

SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

SARS-CoV-2 Membrane Protein: From Genomic Data to Structural New Insights

Conserved Targets to Prevent Emerging Coronaviruses

Electrostatic Map of the SARS-CoV-2 Virion Specifies Binding Sites of the Antiviral Cationic Photosensitizer

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