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1.
J Phys Chem Lett ; 12(51): 12249-12255, 2021 Dec 30.
Article in English | MEDLINE | ID: covidwho-1586057

ABSTRACT

SARS-CoV-2 and other coronaviruses pose major threats to global health, yet computational efforts to understand them have largely overlooked the process of budding, a key part of the coronavirus life cycle. When expressed together, coronavirus M and E proteins are sufficient to facilitate budding into the ER-Golgi intermediate compartment (ERGIC). To help elucidate budding, we ran atomistic molecular dynamics (MD) simulations using the Feig laboratory's refined structural models of the SARS-CoV-2 M protein dimer and E protein pentamer. Our MD simulations consisted of M protein dimers and E protein pentamers in patches of membrane. By examining where these proteins induced membrane curvature in silico, we obtained insights around how the budding process may occur. Multiple M protein dimers acted together to induce global membrane curvature through protein-lipid interactions while E protein pentamers kept the membrane planar. These results could eventually help guide development of antiviral therapeutics that inhibit coronavirus budding.


Subject(s)
Coronavirus Envelope Proteins/metabolism , Molecular Dynamics Simulation , SARS-CoV-2/physiology , Viral Matrix Proteins/metabolism , COVID-19/pathology , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Endoplasmic Reticulum/metabolism , Golgi Apparatus/metabolism , Humans , Protein Multimerization , Protein Transport , SARS-CoV-2/isolation & purification , Viral Matrix Proteins/chemistry
2.
Sci Rep ; 11(1): 20383, 2021 10 14.
Article in English | MEDLINE | ID: covidwho-1469988

ABSTRACT

SARS-CoV-2 continues to infect an ever-expanding number of people, resulting in an increase in the number of deaths globally. With the emergence of new variants, there is a corresponding decrease in the currently available vaccine efficacy, highlighting the need for greater insights into the viral epitope profile for both vaccine design and assessment. In this study, three immunodominant linear B cell epitopes in the SARS-CoV-2 spike receptor-binding domain (RBD) were identified by immunoinformatics prediction, and confirmed by ELISA with sera from Macaca fascicularis vaccinated with a SARS-CoV-2 RBD subunit vaccine. Further immunoinformatics analyses of these three epitopes gave rise to a method of linear B cell epitope prediction and selection. B cell epitopes in the spike (S), membrane (M), and envelope (E) proteins were subsequently predicted and confirmed using convalescent sera from COVID-19 infected patients. Immunodominant epitopes were identified in three regions of the S2 domain, one region at the S1/S2 cleavage site and one region at the C-terminus of the M protein. Epitope mapping revealed that most of the amino acid changes found in variants of concern are located within B cell epitopes in the NTD, RBD, and S1/S2 cleavage site. This work provides insights into B cell epitopes of SARS-CoV-2 as well as immunoinformatics methods for B cell epitope prediction, which will improve and enhance SARS-CoV-2 vaccine development against emergent variants.


Subject(s)
COVID-19/immunology , Epitopes, B-Lymphocyte/immunology , Immunodominant Epitopes/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Viral Matrix Proteins/immunology , Animals , COVID-19/prevention & control , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Computational Biology , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/immunology , Epitopes, B-Lymphocyte/chemistry , Humans , Immunoassay , Immunodominant Epitopes/chemistry , Macaca , Models, Molecular , Spike Glycoprotein, Coronavirus/chemistry , Viral Matrix Proteins/chemistry
3.
Mol Syst Biol ; 17(9): e10079, 2021 09.
Article in English | MEDLINE | ID: covidwho-1406892

ABSTRACT

We modeled 3D structures of all SARS-CoV-2 proteins, generating 2,060 models that span 69% of the viral proteome and provide details not available elsewhere. We found that ˜6% of the proteome mimicked human proteins, while ˜7% was implicated in hijacking mechanisms that reverse post-translational modifications, block host translation, and disable host defenses; a further ˜29% self-assembled into heteromeric states that provided insight into how the viral replication and translation complex forms. To make these 3D models more accessible, we devised a structural coverage map, a novel visualization method to show what is-and is not-known about the 3D structure of the viral proteome. We integrated the coverage map into an accompanying online resource (https://aquaria.ws/covid) that can be used to find and explore models corresponding to the 79 structural states identified in this work. The resulting Aquaria-COVID resource helps scientists use emerging structural data to understand the mechanisms underlying coronavirus infection and draws attention to the 31% of the viral proteome that remains structurally unknown or dark.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Host-Pathogen Interactions/genetics , Protein Processing, Post-Translational , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Transport Systems, Neutral/chemistry , Amino Acid Transport Systems, Neutral/genetics , Amino Acid Transport Systems, Neutral/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Binding Sites , COVID-19/genetics , COVID-19/metabolism , COVID-19/virology , Computational Biology/methods , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/metabolism , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Nucleocapsid Proteins/metabolism , Humans , Mitochondrial Membrane Transport Proteins/chemistry , Mitochondrial Membrane Transport Proteins/genetics , Mitochondrial Membrane Transport Proteins/metabolism , Models, Molecular , Molecular Mimicry , Neuropilin-1/chemistry , Neuropilin-1/genetics , Neuropilin-1/metabolism , Phosphoproteins/chemistry , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Protein Interaction Mapping/methods , Protein Multimerization , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics , Viral Matrix Proteins/metabolism , Viroporin Proteins/chemistry , Viroporin Proteins/genetics , Viroporin Proteins/metabolism , Virus Replication
4.
J Chem Theory Comput ; 17(10): 6483-6490, 2021 Oct 12.
Article in English | MEDLINE | ID: covidwho-1404872

ABSTRACT

SARS-CoV-2 that caused COVID-19 has spread since the end of 2019. Its major effects resulted in over four million deaths around the whole world by August 2021. Therefore, understanding virulence mechanisms is important to prevent future outbreaks and for COVID-19 drug development. The envelope (E) protein is an important structural protein, affecting virus assembly and budding. The E protein pentamer is a viroporin, serving as an ion transferring channel in cells. In this work, we applied molecular dynamic simulations and topological and electrostatic analyses to study the effects of palmitoylation on the E protein pentamer. The results indicate that the cation transferring direction is more from the lumen to the cytosol. The structure of the palmitoylated E protein pentamer is more stable while the loss of palmitoylation caused the pore radius to reduce and even collapse. The electrostatic forces on the two sides of the palmitoylated E protein pentamer are more beneficial to attract cations in the lumen and to release cations into the cytosol. The results indicate the importance of palmitoylation, which can help the drug design for the treatment of COVID-19.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Lipoylation , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cations/chemistry , Computational Biology , Cytosol/chemistry , Drug Design , Humans , Models, Molecular , Molecular Dynamics Simulation , Molecular Structure , Principal Component Analysis , Protons , Static Electricity
6.
Nat Struct Mol Biol ; 27(12): 1202-1208, 2020 12.
Article in English | MEDLINE | ID: covidwho-1387444

ABSTRACT

An essential protein of the SARS-CoV-2 virus, the envelope protein E, forms a homopentameric cation channel that is important for virus pathogenicity. Here we report a 2.1-Å structure and the drug-binding site of E's transmembrane domain (ETM), determined using solid-state NMR spectroscopy. In lipid bilayers that mimic the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membrane, ETM forms a five-helix bundle surrounding a narrow pore. The protein deviates from the ideal α-helical geometry due to three phenylalanine residues, which stack within each helix and between helices. Together with valine and leucine interdigitation, these cause a dehydrated pore compared with the viroporins of influenza viruses and HIV. Hexamethylene amiloride binds the polar amino-terminal lumen, whereas acidic pH affects the carboxy-terminal conformation. Thus, the N- and C-terminal halves of this bipartite channel may interact with other viral and host proteins semi-independently. The structure sets the stage for designing E inhibitors as antiviral drugs.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Lipid Bilayers/chemistry , SARS-CoV-2/chemistry , Amantadine/chemistry , Amiloride/analogs & derivatives , Amiloride/chemistry , Antiviral Agents/chemistry , Coronavirus Envelope Proteins/genetics , Dimyristoylphosphatidylcholine/chemistry , Hydrogen-Ion Concentration , Magnetic Resonance Spectroscopy , Models, Molecular , Phenylalanine/chemistry , Phospholipids/chemistry , Protein Conformation , Protein Domains , SARS-CoV-2/genetics
7.
Med Hypotheses ; 145: 110342, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-1386307

ABSTRACT

This study aimed at identifying human neural proteins that can be attacked by cross-reacting SARS-COV-2 antibodies causing Guillain-Barré syndrome. These markers can be used for the diagnosis of Guillain-Barré syndrome (GBS). To achieve this goal, proteins implicated in the development of GBS were retrieved from literature. These human proteins were compared to SARS-COV-2 surface proteins to identify homologous sequences using Blastp. Then, MHC-I and MHC-II epitopes were determined in the homologous sequences and used for further analysis. Similar human and SARS-COV-2 epitopes were docked to the corresponding MHC molecule to compare the binding pattern of human and SARS-COV-2 proteins to the MHC molecule. Neural cell adhesion molecule is the only neural protein that showed homologous sequence to SARS-COV-2 envelope protein. The homologous sequence was part of HLA-A68 and HLA-DQA/HLA-DQB epitopes had a similar binding pattern to SARS-COV-2 envelope protein. Based on these results, the study suggests that NCAM may play a significant role in the immunopathogenesis of GBS. NCAM antibodies can be used as a marker for Guillain-Barré syndrome. However, more experimental studies are needed to prove these results.


Subject(s)
CD56 Antigen/chemistry , Coronavirus Envelope Proteins/chemistry , Guillain-Barre Syndrome/immunology , SARS-CoV-2 , Viral Proteins/chemistry , Amino Acid Motifs , COVID-19/immunology , Computational Biology , Computer Simulation , Crystallography, X-Ray , Epitopes/chemistry , HLA-A Antigens/chemistry , HLA-DQ alpha-Chains/chemistry , HLA-DQ beta-Chains/chemistry , Humans , Major Histocompatibility Complex , Models, Theoretical , Peptides/chemistry , Protein Binding
8.
Commun Biol ; 4(1): 724, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1265978

ABSTRACT

SARS-CoV-2 infection leads to coronavirus disease 2019 (COVID-19), which is associated with severe and life-threatening pneumonia and respiratory failure. However, the molecular basis of these symptoms remains unclear. SARS-CoV-1 E protein interferes with control of cell polarity and cell-cell junction integrity in human epithelial cells by binding to the PALS1 PDZ domain, a key component of the Crumbs polarity complex. We show that C-terminal PDZ binding motifs of SARS-CoV-1 and SARS-CoV-2 E proteins bind the PALS1 PDZ domain with 29.6 and 22.8 µM affinity, whereas the related sequence from MERS-CoV did not bind. We then determined crystal structures of PALS1 PDZ domain bound to both SARS-CoV-1 and SARS-CoV-2 E protein PDZ binding motifs. Our findings establish the structural basis for SARS-CoV-1/2 mediated subversion of Crumbs polarity signalling and serve as a platform for the development of small molecule inhibitors to suppress SARS-CoV-1/2 mediated disruption of polarity signalling in epithelial cells.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Membrane Proteins/chemistry , Membrane Proteins/metabolism , Nucleoside-Phosphate Kinase/chemistry , Nucleoside-Phosphate Kinase/metabolism , PDZ Domains , Amino Acid Sequence , Humans , Models, Molecular , Protein Binding
9.
Nat Commun ; 12(1): 3433, 2021 06 08.
Article in English | MEDLINE | ID: covidwho-1261998

ABSTRACT

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created global health and economic emergencies. SARS-CoV-2 viruses promote their own spread and virulence by hijacking human proteins, which occurs through viral protein recognition of human targets. To understand the structural basis for SARS-CoV-2 viral-host protein recognition, here we use cryo-electron microscopy (cryo-EM) to determine a complex structure of the human cell junction protein PALS1 and SARS-CoV-2 viral envelope (E) protein. Our reported structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains of PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce E-mediated virulence.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Intercellular Junctions/metabolism , Membrane Proteins/metabolism , Nucleoside-Phosphate Kinase/metabolism , Amino Acid Sequence , Coronavirus Envelope Proteins/ultrastructure , Cryoelectron Microscopy , Humans , Protein Domains , SARS-CoV-2/physiology , Structural Homology, Protein , Structure-Activity Relationship
10.
Virulence ; 12(1): 1209-1226, 2021 12.
Article in English | MEDLINE | ID: covidwho-1242086

ABSTRACT

New SARS-CoV-2 mutants have been continuously indentified with enhanced transmission ever since its outbreak in early 2020. As an RNA virus, SARS-CoV-2 has a high mutation rate due to the low fidelity of RNA polymerase. To study the single nucleotide polymorphisms (SNPs) dynamics of SARS-CoV-2, 158 SNPs with high confidence were identified by deep meta-transcriptomic sequencing, and the most common SNP type was C > T. Analyses of intra-host population diversity revealed that intra-host quasispecies' composition varies with time during the early onset of symptoms, which implicates viral evolution during infection. Network analysis of co-occurring SNPs revealed the most abundant non-synonymous SNP 22,638 in the S glycoprotein RBD region and 28,144 in the ORF8 region. Furthermore, SARS-CoV-2 variations differ in an individual's respiratory tissue (nose, throat, BALF, or sputum), suggesting independent compartmentalization of SARS-CoV-2 populations in patients. The positive selection analysis of the SARS-CoV-2 genome uncovered the positive selected amino acid G251V on ORF3a. Alternative allele frequency spectrum (AAFS) of all variants revealed that ORF8 could bear alternate alleles with high frequency. Overall, the results show the quasispecies' profile of SARS-CoV-2 in the respiratory tract in the first two months after the outbreak.


Subject(s)
Phylogeny , Polymorphism, Single Nucleotide , Quasispecies , SARS-CoV-2/classification , SARS-CoV-2/genetics , Adult , Aged , Aged, 80 and over , Alleles , COVID-19/virology , Computational Biology , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Female , Gene Frequency , Genome, Viral , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Severity of Illness Index , Young Adult
11.
PLoS Pathog ; 17(5): e1009519, 2021 05.
Article in English | MEDLINE | ID: covidwho-1232468

ABSTRACT

SARS-CoV-2 is the novel coronavirus that is the causative agent of COVID-19, a sometimes-lethal respiratory infection responsible for a world-wide pandemic. The envelope (E) protein, one of four structural proteins encoded in the viral genome, is a 75-residue integral membrane protein whose transmembrane domain exhibits ion channel activity and whose cytoplasmic domain participates in protein-protein interactions. These activities contribute to several aspects of the viral replication-cycle, including virion assembly, budding, release, and pathogenesis. Here, we describe the structure and dynamics of full-length SARS-CoV-2 E protein in hexadecylphosphocholine micelles by NMR spectroscopy. We also characterized its interactions with four putative ion channel inhibitors. The chemical shift index and dipolar wave plots establish that E protein consists of a long transmembrane helix (residues 8-43) and a short cytoplasmic helix (residues 53-60) connected by a complex linker that exhibits some internal mobility. The conformations of the N-terminal transmembrane domain and the C-terminal cytoplasmic domain are unaffected by truncation from the intact protein. The chemical shift perturbations of E protein spectra induced by the addition of the inhibitors demonstrate that the N-terminal region (residues 6-18) is the principal binding site. The binding affinity of the inhibitors to E protein in micelles correlates with their antiviral potency in Vero E6 cells: HMA ≈ EIPA > DMA >> Amiloride, suggesting that bulky hydrophobic groups in the 5' position of the amiloride pyrazine ring play essential roles in binding to E protein and in antiviral activity. An N15A mutation increased the production of virus-like particles, induced significant chemical shift changes from residues in the inhibitor binding site, and abolished HMA binding, suggesting that Asn15 plays a key role in maintaining the protein conformation near the binding site. These studies provide the foundation for complete structure determination of E protein and for structure-based drug discovery targeting this protein.


Subject(s)
Amiloride/pharmacology , COVID-19/drug therapy , Coronavirus Envelope Proteins/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , Amiloride/pharmacokinetics , Animals , Antiviral Agents/pharmacology , Binding Sites/drug effects , COVID-19/virology , Chlorocebus aethiops , Coronavirus Envelope Proteins/chemistry , Humans , Ion Channels/metabolism , Nuclear Magnetic Resonance, Biomolecular , Protein Binding/drug effects , Protein Conformation/drug effects , Protein Domains , Vero Cells , Virus Assembly/drug effects
12.
J Med Virol ; 93(1): 499-505, 2021 01.
Article in English | MEDLINE | ID: covidwho-1206790

ABSTRACT

The initial cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) occurred in Wuhan, China, in December 2019 and swept the world by 23 June 2020 with 8 993 659 active cases, 469 587 deaths across 216 countries, areas or territories. This strongly implies global transmission occurred before the lockdown of China. However, the initial source's transmission routes of SARS-CoV-2 remain obscure and controversial. Research data suggest bat (RaTG13) and pangolin carried CoV were the proximal source of SARS-CoV-2. In this study, we used systematic phylogenetic analysis of Coronavirinae subfamily along with wild type human SARS-CoV, MERS-CoV, and SARS-CoV-2 strains. The key residues of the receptor-binding domain (RBD) and O-linked glycan were compared. SARS-CoV-2 strains were clustered with RaTG13 (97.41% identity), Pangolin-CoV (92.22% identity) and Bat-SL-CoV (80.36% identity), forms a new clade-2 in lineage B of beta-CoV. The alignments of RBD contact residues to ACE2 justified? Those SARS-CoV-2 strains sequences were 100% identical by each other, significantly varied in RaTG13 and pangolin-CoV. SARS-CoV-2 has a polybasic cleavage site with an inserted sequence of PRRA compared to RaTG13 and only PRR to pangolin. Only serine (Ser) in pangolin and both threonine (Thr) and serine (Ser) O-linked glycans were seen in RaTG13, suggesting that a detailed study needed in pangolin (Manis javanica) and bat (Rhinolophus affinis) related CoV.


Subject(s)
Chiroptera/virology , Coronavirus/genetics , Pangolins/virology , Polysaccharides/chemistry , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Animals , Binding Sites , China , Communicable Disease Control , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Gene Expression Regulation, Viral , Host Specificity , Humans , Models, Molecular , Phylogeny , Polysaccharides/metabolism , Protein Conformation , Spike Glycoprotein, Coronavirus/chemistry
13.
Genome ; 64(7): 665-678, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1166573

ABSTRACT

SARS-CoV-2 is mutating and creating divergent variants across the world. An in-depth investigation of the amino acid substitutions in the genomic signature of SARS-CoV-2 proteins is highly essential for understanding its host adaptation and infection biology. A total of 9587 SARS-CoV-2 structural protein sequences collected from 49 different countries are used to characterize protein-wise variants, substitution patterns (type and location), and major substitution changes. The majority of the substitutions are distinct, mostly in a particular location, and lead to a change in an amino acid's biochemical properties. In terms of mutational changes, envelope (E) and membrane (M) proteins are relatively more stable than nucleocapsid (N) and spike (S) proteins. Several co-occurrence substitutions are observed, particularly in S and N proteins. Substitution specific to active sub-domains reveals that heptapeptide repeat, fusion peptides, transmembrane in S protein, and N-terminal and C-terminal domains in the N protein are remarkably mutated. We also observe a few deleterious mutations in the above domains. The overall study on non-synonymous mutation in structural proteins of SARS-CoV-2 at the start of the pandemic indicates a diversity amongst virus sequences.


Subject(s)
SARS-CoV-2/chemistry , Viral Structural Proteins/chemistry , Viral Structural Proteins/genetics , Amino Acid Substitution , Amino Acids/chemistry , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Humans , Mutation , Mutation Rate , Phosphoproteins/chemistry , Phosphoproteins/genetics , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/chemistry , Viral Matrix Proteins/genetics
14.
Protein Sci ; 30(6): 1114-1130, 2021 06.
Article in English | MEDLINE | ID: covidwho-1162948

ABSTRACT

The COVID-19 epidemic is one of the most influential epidemics in history. Understanding the impact of coronaviruses (CoVs) on host cells is very important for disease treatment. The SARS-CoV-2 envelope (E) protein is a small structural protein involved in many aspects of the viral life cycle. The E protein promotes the packaging and reproduction of the virus, and deletion of this protein weakens or even abolishes the virulence. This review aims to establish new knowledge by combining recent advances in the study of the SARS-CoV-2 E protein and by comparing it with the SARS-CoV E protein. The E protein amino acid sequence, structure, self-assembly characteristics, viroporin mechanisms and inhibitors are summarized and analyzed herein. Although the mechanisms of the SARS-CoV-2 and SARS-CoV E proteins are similar in many respects, specific studies on the SARS-CoV-2 E protein, for both monomers and oligomers, are still lacking. A comprehensive understanding of this protein should prompt further studies on the design and characterization of effective targeted therapeutic measures.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Envelope Proteins/antagonists & inhibitors , Coronavirus Envelope Proteins/metabolism , SARS-CoV-2/physiology , Amino Acid Sequence , Animals , Antiviral Agents/chemistry , COVID-19/metabolism , COVID-19/virology , Coronavirus Envelope Proteins/chemistry , Humans , Models, Molecular , Protein Conformation , SARS-CoV-2/chemistry , SARS-CoV-2/drug effects , Sequence Alignment , Viroporin Proteins/antagonists & inhibitors , Viroporin Proteins/chemistry , Viroporin Proteins/metabolism
15.
J Chem Inf Model ; 60(12): 5853-5865, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-1065772

ABSTRACT

Tremendous effort has been given to the development of diagnostic tests, preventive vaccines, and therapeutic medicines for coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much of this development has been based on the reference genome collected on January 5, 2020. Based on the genotyping of 15 140 genome samples collected up to June 1, 2020, we report that SARS-CoV-2 has undergone 8309 single mutations which can be clustered into six subtypes. We introduce mutation ratio and mutation h-index to characterize the protein conservativeness and unveil that SARS-CoV-2 envelope protein, main protease, and endoribonuclease protein are relatively conservative, while SARS-CoV-2 nucleocapsid protein, spike protein, and papain-like protease are relatively nonconservative. In particular, we have identified mutations on 40% of nucleotides in the nucleocapsid gene in the population level, signaling potential impacts on the ongoing development of COVID-19 diagnosis, vaccines, and antibody and small-molecular drugs.


Subject(s)
COVID-19 , SARS-CoV-2/classification , SARS-CoV-2/metabolism , Antibodies, Viral/metabolism , COVID-19/diagnosis , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/therapy , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Coronavirus Nucleocapsid Proteins/chemistry , Coronavirus Nucleocapsid Proteins/genetics , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/genetics , Endoribonucleases/chemistry , Endoribonucleases/genetics , Genome, Viral , Genotype , Geography , Humans , Mutant Proteins/chemistry , Mutant Proteins/genetics , Mutation , Phosphoproteins/chemistry , Phosphoproteins/genetics , Protein Conformation , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Vaccines/metabolism , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/genetics
16.
Viruses ; 13(2)2021 02 04.
Article in English | MEDLINE | ID: covidwho-1063428

ABSTRACT

Monitoring acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity and emerging mutations in this ongoing pandemic is crucial for understanding its evolution and assuring the performance of diagnostic tests, vaccines, and therapies against coronavirus disease (COVID-19). This study reports on the amino acid (aa) conservation degree and the global and regional temporal evolution by epidemiological week for each residue of the following four structural SARS-CoV-2 proteins: spike, envelope, membrane, and nucleocapsid. All, 105,276 worldwide SARS-CoV-2 complete and partial sequences from 117 countries available in the Global Initiative on Sharing All Influenza Data (GISAID) from 29 December 2019 to 12 September 2020 were downloaded and processed using an in-house bioinformatics tool. Despite the extremely high conservation of SARS-CoV-2 structural proteins (>99%), all presented aa changes, i.e., 142 aa changes in 65 of the 75 envelope aa, 291 aa changes in 165 of the 222 membrane aa, 890 aa changes in 359 of the 419 nucleocapsid aa, and 2671 changes in 1132 of the 1273 spike aa. Mutations evolution differed across geographic regions and epidemiological weeks (epiweeks). The most prevalent aa changes were D614G (81.5%) in the spike protein, followed by the R203K and G204R combination (37%) in the nucleocapsid protein. The presented data provide insight into the genetic variability of SARS-CoV-2 structural proteins during the pandemic and highlights local and worldwide emerging aa changes of interest for further SARS-CoV-2 structural and functional analysis.


Subject(s)
COVID-19/virology , Coronavirus Envelope Proteins/genetics , Coronavirus Nucleocapsid Proteins/genetics , Evolution, Molecular , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Viral Matrix Proteins/genetics , Amino Acid Substitution , COVID-19/epidemiology , Coronavirus Envelope Proteins/chemistry , Coronavirus Nucleocapsid Proteins/chemistry , Genetic Variation , Genome, Viral , Humans , Mutation , Pandemics , Phosphoproteins/chemistry , Phosphoproteins/genetics , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Viral Matrix Proteins/chemistry
17.
Int J Biol Macromol ; 172: 74-81, 2021 Mar 01.
Article in English | MEDLINE | ID: covidwho-1002618

ABSTRACT

COVID-19 is one of the fatal pandemic throughout the world. For cellular fusion, its antigenic peptides are presented by major histocompatibility complex (MHC) in humans. Therefore, exploration into residual interaction details of CoV2 with MHCs shall be a promising point for instigating the vaccine development. Envelope (E) protein, the smallest outer surface protein from SARS-CoV2 genome was found to possess the highest antigenicity and is therefore used to identify B-cell and T-cell epitopes. Four novel mutations (T55S, V56F, E69R and G70del) were observed in E-protein of SARS-CoV2 after evolutionary analysis. It showed a coil➔helix transition in the protein conformation. Antigenic variability of the epitopes was also checked to explore the novel mutations in the epitope region. It was found that the interactions were more when SARS-CoV2 E-protein interacted with MHC-I than with MHC-II through several ionic and H-bonds. Tyr42 and Tyr57 played a predominant role upon interaction with MHC-I. The higher ΔG values with lesser dissociation constant values also affirm the stronger and spontaneous interaction by SARS-CoV2 proteins with MHCs. On comparison with the consensus E-protein, SARS-CoV2 E-protein showed stronger interaction with the MHCs with lesser solvent accessibility. E-protein can therefore be targeted as a potential vaccine target against SARS-CoV2.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , Coronavirus Envelope Proteins/immunology , Evolution, Molecular , Molecular Docking Simulation , SARS-CoV-2/immunology , Amino Acid Sequence , Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/genetics , Epitopes, B-Lymphocyte/chemistry , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/immunology , Humans , Hydrogen Bonding , Kinetics , Mutation/genetics , Phylogeny , Protein Binding , Solvents , Thermodynamics , Viral Vaccines/immunology
18.
Exp Eye Res ; 203: 108433, 2021 02.
Article in English | MEDLINE | ID: covidwho-1002524

ABSTRACT

Although severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) infection have emerged globally, findings related to ocular involvement and reported cases are quite limited. Immune reactions against viral infections are closely related to viral and host proteins sequence similarity. Molecular Mimicry has been described for many different viruses; sequence similarities of viral and human tissue proteins may trigger autoimmune reactions after viral infections due to similarities between viral and human structures. With this study, we aimed to investigate the protein sequence similarity of SARS CoV-2 with retinal proteins and retinal pigment epithelium (RPE) surface proteins. Retinal proteins involved in autoimmune retinopathy and retinal pigment epithelium surface transport proteins were analyzed in order to infer their structural similarity to surface glycoprotein (S), nucleocapsid phosphoprotein (N), membrane glycoprotein (M), envelope protein (E), ORF1ab polyprotein (orf1ab) proteins of SARS CoV-2. Protein similarity comparisons, 3D protein structure prediction, T cell epitopes-MHC binding prediction, B cell epitopes-MHC binding prediction and the evaluation of the antigenicity of peptides assessments were performed. The protein sequence analysis was made using the Pairwise Sequence Alignment and the LALIGN program. 3D protein structure estimates were made using Swiss Model with default settings and analyzed with TM-align web server. T-cell epitope identification was performed using the Immune Epitope Database and Analysis (IEDB) resource Tepitool. B cell epitopes based on sequence characteristics of the antigen was performed using amino acid scales and HMMs with the BepiPred 2.0 web server. The predicted peptides/epitopes in terms of antigenicity were examined using the default settings with the VaxiJen v2.0 server. Analyses showed that, there is a meaningful similarities between 6 retinal pigment epithelium surface transport proteins (MRP-4, MRP-5, RFC1, SNAT7, TAUT and MATE) and the SARS CoV-2 E protein. Immunoreactive epitopic sites of these proteins which are similar to protein E epitope can create an immune stimulation on T cytotoxic and T helper cells and 6 of these 9 epitopic sites are also vaxiJen. These result imply that autoimmune cross-reaction is likely between the studied RPE proteins and SARS CoV-2 E protein. The structure of SARS CoV-2, its proteins and immunologic reactions against these proteins remain largely unknown. Understanding the structure of SARS CoV-2 proteins and demonstration of similarity with human proteins are crucial to predict an autoimmune response associated with immunity against host proteins and its clinical manifestations as well as possible adverse effects of vaccination.


Subject(s)
Amino Acid Sequence , Autoimmune Diseases/virology , Eye Proteins/chemistry , Retinal Diseases/virology , SARS-CoV-2/chemistry , Sequence Homology , Viral Proteins/chemistry , COVID-19/epidemiology , Computational Biology , Coronavirus Envelope Proteins/chemistry , Coronavirus Nucleocapsid Proteins/chemistry , Eye Infections, Viral/virology , Humans , Membrane Glycoproteins/chemistry , Phosphoproteins/chemistry , Polyproteins/chemistry , Retinal Pigment Epithelium/chemistry , Viral Matrix Proteins/chemistry
19.
Phys Rev E ; 102(5-1): 052408, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-947704

ABSTRACT

Ion flow inside an ion channel can be described through continuum based Born-Poisson-Nernst-Planck (BPNP) equations in conjunction with the Lennard-Jones potential. Keeping in mind the ongoing pandemic, in this study, an attempt has been made to understand the selectivity and the current voltage relation of the COVID-19 E protein pentameric ion channel. Two ionic species, namely Na^{+} and Cl^{-}, have been considered here. E protein is one of the smallest structural protein which is embedded in the outer membrane of the virus. Once the virus is inside the host cell, this protein is expressed abundantly and is responsible for activities such as replication and budding of the virus. In the literature, we can find a few experimental studies focusing on understanding the activity of the channel formed by E proteins of different viruses. Here, we attempt the same study for the COVID-19 E protein ion channel through mathematical modeling. The channel geometry is calculated from the protein data bank file which was provided by NARLabs, Taiwan, using the hole program. Further, it was used to obtain the charge distribution using the pdbtopqr online program. The immersed boundary-lattice Boltzmann method (IB-LBM) has been implemented to numerically solve the system of equations in the channel generated by the protein data bank file. Further, an in-house code which operates on multiple GPUs and uses the cuda platform has been developed to achieve the goal of performing the current investigation.


Subject(s)
Coronavirus Envelope Proteins/chemistry , Coronavirus Envelope Proteins/metabolism , Models, Molecular , Protein Multimerization , Biological Transport , Protein Structure, Quaternary
20.
Genomics ; 112(6): 3890-3892, 2020 11.
Article in English | MEDLINE | ID: covidwho-632102

ABSTRACT

In the NCBI database, as on June 6, 2020, total number of available complete genome sequences of SARS-CoV2 across the world is 3617. The envelope (E) protein of SARS-CoV2 possesses several non-synonymous mutations over the transmembrane and C-terminus domains in 15 (0.414%) genomes among 3617 SARS-CoV2 genomes, analyzed. More precisely, 10(0.386%) out of 2588 genomes from the USA, 3(0.806%) from Asia, 1 (0.348%) from Europe and 1 (0.274%) from Oceania contained the missense mutations over the E-protein of SARS-CoV2 genomes. The C-terminus motif DLLV has been to DFLV and YLLV in the proteins from QJR88103 (Australia: Victoria) and QKI36831 (China: Guangzhou) respectively, which might affect the binding of this motif with the host protein PALS1.


Subject(s)
COVID-19/virology , Coronavirus Envelope Proteins/genetics , Coronavirus Envelope Proteins/metabolism , Mutation , SARS-CoV-2/genetics , Coronavirus Envelope Proteins/chemistry , Genome, Viral , Humans , Membrane Proteins/metabolism , Nucleoside-Phosphate Kinase/metabolism , SARS-CoV-2/isolation & purification
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