The outbreak of COVID-19 across the world has posed unprecedented and global challenges on multiple fronts. Most of the vaccine and drug development has focused on the spike proteins and viral RNA-polymerases and main protease for viral replication. Using the bioinformatics and structural modelling approach, we modelled the structure of the envelope (E)-protein of novel SARS-CoV-2. The E-protein of this virus shares sequence similarity with that of SARS-CoV-1, and is highly conserved in the N-terminus regions. Incidentally, compared to spike proteins, E proteins demonstrate lower disparity and mutability among the isolated sequences. Using homology modelling, we found that the most favorable structure could function as a gated ion channel conducting H + ions. Combining pocket estimation and docking with water, we determined that GLU 8 and ASN 15 in the N-terminal region were in close proximity to form H-bonds which was further validated by insertion of the E protein in an ERGIC-mimic membrane. Additionally, two distinct "core" structures were visible, the hydrophobic core and the central core, which may regulate the opening/closing of the channel. We propose this as a mechanism of viral ion channeling activity which plays a critical role in viral infection and pathogenesis. In addition, it provides a structural basis and additional avenues for vaccine development and generating therapeutic interventions against the virus.

COVID-19 is caused by SARS-CoV-2 which has so far affected more than 500 million people worldwide and killed over 6 million as of 1 May 2022. The approved emergency-use vaccines were lifesaving in such a devastating pandemic. Inflammation-related pathways have been well documented to be upregulated in the case of SARS-CoV-2 in rodents, non-human primates and human samples. We reanalysed a previously published dataset to understand if certain molecular components of inflammation could be higher in infected samples. Mechanistically, viroporins are important players in the life cycle of SARS-CoV-2 and are primary to its pathogenesis. We studied the two prominent viroporins of SARS-CoV-2 (i) Orf3a and (ii) envelope (E) protein from a sequence and structural point of view. Orf3a is a cation-selective viral ion channel which has been shown to disrupt the endosomal pathways. E protein is one of the most conserved proteins among the SARS-CoV proteome which affects the ERGIC-related pathways. The aqueous medium through the viroporins mediates the non-selective translocation of cations, affecting ionic homeostasis in the host cellular compartments. We hypothesize a possible mechanistic approach whereby the ionic imbalance caused by viroporin action could potentially be one of the major pathogenic drivers leading to the increased inflammatory response in the host cell. Our results shed light into the transcriptomic, genomic and structural proteomics aspects of widely studied SARS-CoV-2 viroporins, which can be potentially leveraged for the development of antiviral therapeutics.

The outbreak of COVID-19 across the world has posed unprecedented and global challenges on multiple fronts. Most of the vaccine and drug development has focused on the spike proteins and viral RNA-polymerases. Using the bioinformatics and structural modeling approach, we modeled the structure of the envelope (E)-protein of novel SARS-CoV-2. The E-protein of this virus shares sequence similarity with that of SARS-CoV-1, and is highly conserved in the N-terminal regions. Incidentally, compared to spike proteins, E proteins demonstrate lower disparity and mutability among the isolated sequences. Using homology modeling, we found that the most favorable structure could function as a gated proton channel. Combining pocket estimation and docking with water, we determined that GLU 8 and ASN 15 in the N-terminal region were in close proximity to form H-bonds. Additionally, two distinct "core" structures were visible, the hydrophobic core and the central core, which may regulate the opening/closing of the channel. We propose this as a mechanism of viral proton channeling activity which may play a critical role in viral infection. In addition, it provides a structural basis and additional avenues for LAV development and generating therapeutic interventions against the virus. Significance StatementStructural modeling of the novel SARS-CoV-2 envelope protein (E-protein) demonstrating its possible proton channeling activity

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COVID-19 is caused by SARS-CoV-2 which has affected nearly 220 million people worldwide and death toll close to 5 million as of present day. The approved vaccines are lifesaving yet temporary solutions to such a devastating pandemic. Viroporins are important players of the viral life cycle of SARS-Cov-2 and one of the primary determinants of its pathogenesis. We studied the two prominent viroporins of SARS-CoV-2 (i) Orf3a and (ii) Envelope (E) protein from a structural point of view. Orf3a has several hotspots of mutations which has been reported in SARS-CoV-2 with respect to SARS-CoV-1. Mutations in SARS-CoV-2 Orf3a channel forming residues enhances the formation of a prominent the inter-subunit channel, which was not present in the SARS-CoV-1 Orf3a. This enhanced structural feature can be correlated with higher channelling activity in SARS-CoV-2 than in SARS-CoV-1. On the other hand, E protein is one of the most conserved protein among the SARS-CoV proteome. We found that the water molecules form networks of electrostatic interactions with the polar residues in the E protein putative wetted condition while no water channel formation was observed in the putative dewetted condition. This aqueous medium mediates the non-selective translocation of cations thus affecting the ionic homeostasis of the host cellular compartments. This ionic imbalance leads to increased inflammatory response in the host cell. Our results shed light into the mechanism of viroporin action, which can be leveraged for the development of antiviral therapeutics. Furthermore, our results corroborate with previously published transcriptomic data from COVID-19 infected lung alveolar cells where inflammatory responses and molecular regulators directly impacted by ion channelling were upregulated. These observations overlap with transcript upregulation observed in diseases having acute lung injury, pulmonary fibrosis and Acute Respiratory Distress Syndrome (ARDS).