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1.
J Med Virol ; 93(12): 6551-6556, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1530181

ABSTRACT

Lineage B.1.617+, also known as G/452R.V3 and now denoted by WHO with the Greek letters δ and κ, is a recently described SARS-CoV-2 variant under investigation first identified in October 2020 in India. As of May 2021, three sublineages labeled as B.1.617.1 (κ), B.1.617.2 (δ), and B.1.617.3 have been already identified, and their potential impact on the current pandemic is being studied. This variant has 13 amino acid changes, three in its spike protein, which are currently of particular concern: E484Q, L452R, and P681R. Here, we report a major effect of the mutations characterizing this lineage, represented by a marked alteration of the surface electrostatic potential (EP) of the receptor-binding domain (RBD) of the spike protein. Enhanced RBD-EP is particularly noticeable in the B.1.617.2 (δ) sublineage, which shows multiple replacements of neutral or negatively charged amino acids with positively charged amino acids. We here hypothesize that this EP change can favor the interaction between the B.1.617+ RBD and the negatively charged ACE2, thus conferring a potential increase in the virus transmission.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , COVID-19/transmission , Humans , Mutation , Protein Structure, Tertiary , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Static Electricity
2.
J Mol Model ; 27(11): 323, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1525539

ABSTRACT

The world has face the COVID-19 pandemic which has already caused millions of death. Due to the urgency in fighting the virus, we study five residues of free amino acids present in the structure of the SARS-CoV-2 spike protein (S). We investigated the spontaneous interaction between amino acids and silver ions (Ag+), considering these ions as a virucide chemical agent for SARS-CoV-2. The amino acid-Ag+ systems were investigated in a gaseous medium and a simulated water environment was described with a continuum model (PCM) the calculations were performed within the framework of density functional theory (DFT). Calculations related to the occupied orbitals of higher energy showed that Ag+ has a tendency to interact with the nitrile groups (-NH). The negative values of the Gibbs free energies show that the interaction process between amino acids-Ag+ in both media occurs spontaneously. There is a decrease in Gibbs free energy from the amino acid-Ag+ interactions immersed in a water solvation simulator.


Subject(s)
Amino Acids/chemistry , Antiviral Agents/chemistry , Density Functional Theory , Silver/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acids/metabolism , Antiviral Agents/metabolism , Binding Sites , Cations, Monovalent , Gene Expression , Humans , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Silver/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics
3.
J Mol Model ; 27(11): 323, 2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1465873

ABSTRACT

The world has face the COVID-19 pandemic which has already caused millions of death. Due to the urgency in fighting the virus, we study five residues of free amino acids present in the structure of the SARS-CoV-2 spike protein (S). We investigated the spontaneous interaction between amino acids and silver ions (Ag+), considering these ions as a virucide chemical agent for SARS-CoV-2. The amino acid-Ag+ systems were investigated in a gaseous medium and a simulated water environment was described with a continuum model (PCM) the calculations were performed within the framework of density functional theory (DFT). Calculations related to the occupied orbitals of higher energy showed that Ag+ has a tendency to interact with the nitrile groups (-NH). The negative values of the Gibbs free energies show that the interaction process between amino acids-Ag+ in both media occurs spontaneously. There is a decrease in Gibbs free energy from the amino acid-Ag+ interactions immersed in a water solvation simulator.


Subject(s)
Amino Acids/chemistry , Antiviral Agents/chemistry , Density Functional Theory , Silver/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acids/metabolism , Antiviral Agents/metabolism , Binding Sites , Cations, Monovalent , Gene Expression , Humans , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , SARS-CoV-2/chemistry , Silver/metabolism , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Static Electricity , Thermodynamics
4.
PLoS One ; 16(9): e0257434, 2021.
Article in English | MEDLINE | ID: covidwho-1443838

ABSTRACT

Although research has shown that the COVID-19 disease is most likely caused by airborne transmission of the SARS-CoV-2 virus, disinfection of potentially contaminated surfaces is also recommended to limit the spread of the disease. Use of electrostatic sprayers (ESS) and foggers to rapidly apply disinfectants over large areas or to complex surfaces has emerged with the COVID-19 pandemic. ESSs are designed to impart an electrostatic charge to the spray droplets with the goal of increasing deposition of the droplets onto surfaces, thereby promoting more efficient use of the disinfectant. The purpose of this research was to evaluate several spray parameters for different types of sprayers and foggers, as they relate to the application of disinfectants. Some of the parameters evaluated included the spray droplet size distribution, the electrostatic charge, the ability of the spray to wrap around objects, and the loss of disinfectant chemical active ingredient due to the spray process. The results show that most of the devices evaluated for droplet size distribution had an average volume median diameter ≥ 40 microns, and that four out of the six ESS tested for charge/mass produced sprays of at least 0.1 mC/kg. A minimal wrap-around effect of the spray deposition onto a cylindrical object was observed. The loss of disinfectant active ingredient to the air due to spraying was minimal for the two disinfectants tested, and concurrently, the active ingredient concentrations of the liquid disinfectants sprayed and collected 3 feet (1 meter) away from the spray nozzle do not decrease.


Subject(s)
COVID-19/prevention & control , Disinfectants/administration & dosage , Disinfection/instrumentation , Disinfectants/pharmacology , Disinfection/methods , Equipment Design , Humans , SARS-CoV-2/drug effects , Static Electricity , Surface Properties/drug effects
5.
Environ Sci Technol ; 55(22): 15351-15360, 2021 11 16.
Article in English | MEDLINE | ID: covidwho-1440445

ABSTRACT

With the COVID-19 pandemic surging, the demand for masks is challenging, especially in less-developed areas across the world. Billions of used masks are threatening the environment as a new source of plastic pollution. In this paper, corona discharge (CD) was explored as a safe and reliable method for mask reuse to alleviate the situation. CD can disinfect masks and simultaneously restore electrostatic charges to prevent filtration efficiency deterioration. Electric field, ions, and reactive species generated by CD cause DNA damage and protein denaturation to effectively disinfect N95 respirators. Log reduction of 2-3 against Escherichia coli can be easily reached within 7.5 min. Log reduction of up to 6 can be reached after three cycles of treatment with optimized parameters. CD disinfection is a broad spectrum with log reduction >1 against yeast and >2.5 against spores. N95 respirators can be recharged within 30 s of treatment and the charges can be retained at a higher level than brand-new masks for at least 5 days. The filtration efficiency of masks was maintained at ∼95% after 15 cycles of treatment. CD can provide at least 10 cycles of safe reuse with benefits of high safety, affordability, accessibility, and device scalability/portability.


Subject(s)
COVID-19 , Disinfection , Humans , N95 Respirators , Pandemics , SARS-CoV-2 , Static Electricity
6.
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
7.
Biochemistry ; 60(39): 2925-2931, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1402014

ABSTRACT

Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (Mpro) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 Mpro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.


Subject(s)
Antiviral Agents/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Isoxazoles/metabolism , Phenylalanine/analogs & derivatives , Pyrrolidinones/metabolism , SARS-CoV-2/enzymology , Valine/analogs & derivatives , Antiviral Agents/chemistry , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemistry , Enterovirus D, Human/enzymology , Hydrogen Bonding , Isoxazoles/chemistry , Phenylalanine/chemistry , Phenylalanine/metabolism , Protein Binding , Pyrrolidinones/chemistry , Static Electricity , Valine/chemistry , Valine/metabolism
8.
J Phys Chem Lett ; 12(16): 4059-4066, 2021 Apr 29.
Article in English | MEDLINE | ID: covidwho-1387120

ABSTRACT

The spike glycoprotein (S-protein) mediates SARS-CoV-2 entry via intermolecular interaction with human angiotensin-converting enzyme 2. The receptor binding domain (RBD) of the S-protein has been considered critical for this interaction and acts as the target of numerous neutralizing antibodies and antiviral peptides. This study used the fragment molecular orbital method to analyze the interactions between the RBD and antibodies/peptides and extracted crucial residues that can be used as epitopes. The interactions evaluated as interfragment interaction energy values between the RBD and 12 antibodies/peptides showed a fairly good correlation with the experimental activity pIC50 (R2 = 0.540). Nine residues (T415, K417, Y421, F456, A475, F486, N487, N501, and Y505) were confirmed as being crucial. Pair interaction energy decomposition analyses showed that hydrogen bonds, electrostatic interactions, and π-orbital interactions are important. Our results provide essential information for understanding SARS-CoV-2-antibody/peptide binding and may play roles in future antibody/antiviral drug design.


Subject(s)
Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/metabolism , Antibodies, Viral/metabolism , Peptides/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , Binding Sites/immunology , Epitopes/immunology , Epitopes/metabolism , Humans , Hydrogen Bonding , Models, Chemical , Protein Binding , Protein Domains , Quantum Theory , SARS-CoV-2/chemistry , Static Electricity
9.
Chempluschem ; 86(7): 972-981, 2021 07.
Article in English | MEDLINE | ID: covidwho-1384145

ABSTRACT

We report the synthesis and characterization of a fullerene-steroid hybrid that contains H2 @C60 and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction with 76 % yield. Theoretical calculations at the DFT-D3(BJ)/PBE 6-311G(d,p) level predict the most stable conformation and that the saturation of a double bond is the main factor causing the upfield shielding of the signal appearing at -3.13 ppm, which corresponds to the H2 located inside the fullerene cage. Relevant stereoelectronic parameters were also investigated and reinforce the idea that electronic interactions must be considered to develop studies on chemical-biological interactions. A molecular docking simulation predicted that the binding energy values for the protease-hybrid complexes were -9.9 kcal/mol and -13.5 kcal/mol for PLpro and 3CLpro respectively, indicating the potential use of the synthesized steroid-H2 @C60 as anti-SARS-Cov-2 agent.


Subject(s)
Androsterone/chemistry , Antiviral Agents/chemistry , Fullerenes/chemistry , Molecular Docking Simulation , SARS-CoV-2/metabolism , Antiviral Agents/metabolism , Binding Sites , COVID-19/pathology , COVID-19/virology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/metabolism , Density Functional Theory , Humans , Protein Binding , SARS-CoV-2/isolation & purification , Static Electricity , Thermodynamics
10.
J Chem Inf Model ; 60(12): 5815-5831, 2020 12 28.
Article in English | MEDLINE | ID: covidwho-1387107

ABSTRACT

Herein, we investigate the structure and flexibility of the hydrated SARS-CoV-2 main protease by means of 2.0 µs molecular dynamics (MD) simulations in explicit solvent. After having performed electrostatic pKa calculations on several X-ray structures, we consider both the native (unbound) configuration of the enzyme and its noncovalent complex with a model peptide, Ace-Ala-Val-Leu-Gln∼Ser-Nme, which mimics the polyprotein sequence recognized at the active site. For each configuration, we also study their monomeric and homodimeric forms. The simulations of the unbound systems show that the relative orientation of domain III is not stable in the monomeric form and provide further details about interdomain motions, protomer-protomer interactions, inter-residue contacts, accessibility at the catalytic site, etc. In the presence of the peptide substrate, the monomeric protease exhibits a stable interdomain arrangement, but the relative orientation between the scissile peptide bond and the catalytic dyad is not favorable for catalysis. By means of comparative analysis, we further assess the catalytic impact of the enzyme dimerization, the actual flexibility of the active site region, and other structural effects induced by substrate binding. Overall, our computational results complement previous crystallographic studies on the SARS-CoV-2 enzyme and, together with other simulation studies, should contribute to outline useful structure-activity relationships.


Subject(s)
COVID-19/metabolism , Coronavirus 3C Proteases/metabolism , Peptides/chemistry , Peptides/metabolism , SARS-CoV-2/metabolism , Amino Acid Sequence , Catalytic Domain , Dimerization , Humans , Molecular Dynamics Simulation , Protein Conformation , Static Electricity , Structure-Activity Relationship , Substrate Specificity , Thermodynamics
11.
Viruses ; 13(8)2021 08 15.
Article in English | MEDLINE | ID: covidwho-1355053

ABSTRACT

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.


Subject(s)
Indoles/metabolism , Middle East Respiratory Syndrome Coronavirus/chemistry , Organometallic Compounds/metabolism , Photosensitizing Agents/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Binding Sites , Indoles/chemistry , Isoindoles , Methylene Blue/metabolism , Models, Molecular , Molecular Dynamics Simulation , Organometallic Compounds/chemistry , Protein Conformation , Protein Domains , Protein Subunits/chemistry , SARS Virus/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity , Zinc Compounds
12.
Brief Bioinform ; 22(2): 1499-1507, 2021 03 22.
Article in English | MEDLINE | ID: covidwho-1352122

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causative agent of the coronavirus disease 2019 (COVID-19) pandemic, is thought to release its RNA genome at either the cell surface or within endosomes, the balance being dependent on spike protein stability, and the complement of receptors, co-receptors and proteases. To investigate possible mediators of pH-dependence, pKa calculations have been made on a set of structures for spike protein ectodomain and fragments from SARS-CoV-2 and other coronaviruses. Dominating a heat map of the aggregated predictions, three histidine residues in S2 are consistently predicted as destabilizing in pre-fusion (all three) and post-fusion (two of the three) structures. Other predicted features include the more moderate energetics of surface salt-bridge interactions and sidechain-mainchain interactions. Two aspartic acid residues in partially buried salt-bridges (D290-R273 and R355-D398) have pKas that are calculated to be elevated and destabilizing in more open forms of the spike trimer. These aspartic acids are most stabilized in a tightly closed conformation that has been observed when linoleic acid is bound, and which also affects the interactions of D614. The D614G mutation is known to modulate the balance of closed to open trimer. It is suggested that D398 in particular contributes to a pH-dependence of the open/closed equilibrium, potentially coupled to the effects of linoleic acid binding and D614G mutation, and possibly also A570D mutation. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.


Subject(s)
Hydrogen-Ion Concentration , SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Amino Acid Sequence , Humans , Protein Conformation , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/chemistry , Static Electricity
13.
J Comput Chem ; 42(26): 1832-1860, 2021 10 05.
Article in English | MEDLINE | ID: covidwho-1321692

ABSTRACT

An adaptive finite element solver for the numerical calculation of the electrostatic coupling between molecules in a solvent environment is developed and tested. At the heart of the solver is a goal-oriented a posteriori error estimate for the electrostatic coupling, derived and implemented in the present work, that gives rise to an orders of magnitude improved precision and a shorter computational time as compared to standard finite difference solvers. The accuracy of the new solver ARGOS is evaluated by numerical experiments on a series of problems with analytically known solutions. In addition, the solver is used to calculate electrostatic couplings between two chromophores, linked to polyproline helices of different lengths and between the spike protein of SARS-CoV-2 and the ACE2 receptor. All the calculations are repeated by using the well-known finite difference solvers MEAD and APBS, revealing the advantages of the present finite element solver.


Subject(s)
Finite Element Analysis , Static Electricity , Algorithms , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Computer Simulation , Humans , Models, Molecular , Protein Binding , SARS-CoV-2/physiology , Solvents/chemistry , Solvents/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics
14.
Arch Virol ; 166(9): 2487-2493, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1298567

ABSTRACT

The safety of personal protective equipment (PPE) is very important, and so is the choice of materials used. The ability of electrostatic charges (ESCs) generated from the friction of engineered materials to attract or repel viruses has a significant impact on their applications. This study examined the ESCs generated on the surface of PPE used by healthcare workers to enhance their potential effectiveness in protecting the wearer from viruses. This is a crucial consideration for the newly emerged severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which has a negative charge. The magnitudes and signs of generated ESCs on the surfaces of the PPE were determined experimentally using an Ultra Stable Surface DC Voltmeter. The high negative ESCs acquired by the polyethylene disposable cap and facemask are expected to repel negatively charged viruses and prevent them from adhering to the outer layer of the material. Also, the choice of polypropylene for facemasks and gowns is excellent because it is an aggressively negatively charged material in the triboelectric series. This property guarantees that facemasks and gowns can repel viruses from the wearer. However, the positive ESCs generated on latex glove surfaces are of great concern because they can attract negatively charged viruses and create a source of infection. In conclusion, it is necessary to ensure that PPE be made of materials whose surfaces develop a negative ESC to repel viruses, as well as to select polyethylene gloves.


Subject(s)
COVID-19/prevention & control , Health Personnel/education , Personal Protective Equipment/virology , SARS-CoV-2/chemistry , COVID-19/transmission , Hair/chemistry , Health Knowledge, Attitudes, Practice , Humans , Latex/chemistry , Materials Testing , Polyethylene/chemistry , Polypropylenes/chemistry , Skin/chemistry , Static Electricity
15.
J Phys Chem B ; 125(27): 7368-7379, 2021 07 15.
Article in English | MEDLINE | ID: covidwho-1297287

ABSTRACT

A structural understanding of the mechanism by which antibodies bind SARS-CoV-2 at the atomic level is highly desirable as it can tell the development of more effective antibodies to treat Covid-19. Here, we use steered molecular dynamics (SMD) and coarse-grained simulations to estimate the binding affinity of the monoclonal antibodies CR3022 and 4A8 to the SARS-CoV-2 receptor-binding domain (RBD) and SARS-CoV-2 N-terminal domain (NTD). Consistent with experiments, our SMD and coarse-grained simulations both indicate that CR3022 has a higher affinity for SARS-CoV-2 RBD than 4A8 for the NTD, and the coarse-grained simulations indicate the former binds three times stronger to its respective epitope. This finding shows that CR3022 is a candidate for Covid-19 therapy and is likely a better choice than 4A8. Energetic decomposition of the interaction energies between these two complexes reveals that electrostatic interactions explain the difference in the observed binding affinity between the two complexes. This result could lead to a new approach for developing anti-Covid-19 antibodies in which good candidates must contain charged amino acids in the area of contact with the virus.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antibodies, Viral , Humans , SARS-CoV-2 , Static Electricity
16.
Proteins ; 89(9): 1158-1166, 2021 09.
Article in English | MEDLINE | ID: covidwho-1296890

ABSTRACT

The 2019-novel coronavirus also known as severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a common threat to animals and humans, and is responsible for the human SARS pandemic in 2019 to 2021. The infection of SARS-CoV-2 in humans involves a viral surface glycoprotein named as spike proteins, which bind to the human angiotensin-converting enzyme 2 (ACE2) proteins. Particularly, the receptor binding domains (RBDs) mediate the interaction and contain several disordered regions, which help in the binding. Investigations on the influence of disordered residues/regions in stability and binding of spike protein with ACE2 help to understand the disease pathogenesis, which has not yet been studied. In this study, we have used molecular-dynamics simulations to characterize the structural changes in disordered regions of the spike protein that result from ACE2 binding. We observed that the disordered regions undergo disorder-to-order transition (DOT) upon binding with ACE2, and the DOT residues are located at functionally important regions of RBD. Although the RBD is having rigid structure, DOT residues make conformational rearrangements for the spike protein to attach with ACE2. The binding is strengthened via hydrophilic and aromatic amino acids mainly present in the DOTs. The positively correlated motions of the DOT residues with its nearby residues also explain the binding profile of RBD with ACE2, and the residues are observed to be contributing more favorable binding energies for the spike-ACE2 complex formation. This study emphasizes that intrinsically disordered residues in the RBD of spike protein may provide insights into its etiology and be useful for drug and vaccine discovery.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , COVID-19/drug therapy , COVID-19/metabolism , Intrinsically Disordered Proteins/chemistry , Intrinsically Disordered Proteins/metabolism , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Humans , Hydrogen Bonding , Molecular Dynamics Simulation , Pliability , Protein Binding , Static Electricity
17.
Sci Rep ; 11(1): 13476, 2021 06 29.
Article in English | MEDLINE | ID: covidwho-1287817

ABSTRACT

Face masks and personal respirators are used to curb the transmission of SARS-CoV-2 in respiratory droplets; filters embedded in some personal protective equipment could be used as a non-invasive sample source for applications, including at-home testing, but information is needed about whether filters are suited to capture viral particles for SARS-CoV-2 detection. In this study, we generated inactivated virus-laden aerosols of 0.3-2 microns in diameter (0.9 µm mean diameter by mass) and dispersed the aerosolized viral particles onto electrostatic face mask filters. The limit of detection for inactivated coronaviruses SARS-CoV-2 and HCoV-NL63 extracted from filters was between 10 to 100 copies/filter for both viruses. Testing for SARS-CoV-2, using face mask filters and nasopharyngeal swabs collected from hospitalized COVID-19-patients, showed that filter samples offered reduced sensitivity (8.5% compared to nasopharyngeal swabs). The low concordance of SARS-CoV-2 detection between filters and nasopharyngeal swabs indicated that number of viral particles collected on the face mask filter was below the limit of detection for all patients but those with the highest viral loads. This indicated face masks are unsuitable to replace diagnostic nasopharyngeal swabs in COVID-19 diagnosis. The ability to detect nucleic acids on face mask filters may, however, find other uses worth future investigation.


Subject(s)
COVID-19/pathology , Masks/virology , Nasopharynx/virology , SARS-CoV-2/isolation & purification , Adult , Aerosols , Aged , COVID-19/virology , Female , Hospitalization , Humans , Limit of Detection , Male , Middle Aged , Particle Size , RNA, Viral/analysis , Real-Time Polymerase Chain Reaction , SARS-CoV-2/physiology , Static Electricity , Viral Load , Young Adult
18.
Sci Rep ; 11(1): 13376, 2021 06 28.
Article in English | MEDLINE | ID: covidwho-1286473

ABSTRACT

MMP-9 plays a number of important physiological functions but is also responsible for many pathological processes, including cancer invasion, metastasis, and angiogenesis. It is, therefore, crucial to understand its enzymatic activity, including activation and inhibition mechanisms. This enzyme may also be partially involved in the "cytokine storm" that is characteristic of COVID-19 disease (SARS-CoV-2), as well as in the molecular mechanisms responsible for lung fibrosis. Due to the variety of processing pathways involving MMP-9 in biological systems and its uniqueness due to the O-glycosylated domain (OGD) and fibronectin-like (FBN) domain, specific interactions with its natural TIMP-1 inhibitor should be carefully studied, because they differ significantly from other homologous systems. In particular, earlier experimental studies have indicated that the newly characterised circular form of a proMMP-9 homotrimer exhibits stronger binding properties to TIMP-1 compared to its monomeric form. However, molecular structures of the complexes and the binding mechanisms remain unknown. The purpose of this study is to fill in the gaps in knowledge. Molecular modelling methods are applied to build the inhibitory and non-inhibitory MMP-9-TIMP-1 complexes, which allows for a detailed description of these structures and should allow for a better understanding of the regulatory processes in which MMP-9 is involved.


Subject(s)
Matrix Metalloproteinase 9/metabolism , Molecular Dynamics Simulation , Tissue Inhibitor of Metalloproteinase-1/metabolism , Enzyme Precursors/chemistry , Enzyme Precursors/metabolism , Humans , Matrix Metalloproteinase 9/chemistry , Protein Binding , Protein Domains , Protein Multimerization , Static Electricity , Tissue Inhibitor of Metalloproteinase-1/antagonists & inhibitors
19.
Anal Bioanal Chem ; 413(29): 7295-7303, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1274805

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents a serious threat to human health all over the world. The development of effective vaccines has been focusing on the spike (S) glycoprotein, which mediates viral invasion to human cells through its interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. In this work, we perform analytical characterization of N- and O-linked glycosylation of the SARS-CoV-2 S glycoprotein. We explore the novel use of dual-functionalized titanium (IV)-immobilized metal affinity chromatography (Ti-IMAC) material for simultaneous enrichment and separation of neutral and sialyl glycopeptides of a recombinant SARS-CoV-2 S glycoprotein from HEK293 cells. This strategy helps eliminate signal suppression from neutral glycopeptides for the detection of sialyl glycopeptides and improves the glycoform coverage of the S protein. We profiled 19 of its 22 potential N-glycosylated sites with 398 unique glycoforms using the dual-functional Ti-IMAC approach, which exhibited improvement of coverage by 1.6-fold compared to the conventional hydrophilic interaction chromatography (HILIC) glycopeptide enrichment method. We also identified O-linked glycosylation site that was not found using the conventional HILIC approach. In addition, we reported on the identification of mannose-6-phosphate (M6P) glycosylation, which substantially expands the current knowledge of the spike protein's glycosylation landscape and enables future investigation into the influence of M6P glycosylation of the spike protein on its cell entry.


Subject(s)
Glycopeptides/isolation & purification , N-Acetylneuraminic Acid/chemistry , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Chromatography, Liquid/methods , Glycopeptides/chemistry , HEK293 Cells , Humans , Mannosephosphates/chemistry , Static Electricity , Tandem Mass Spectrometry/methods
20.
ChemMedChem ; 16(15): 2339-2344, 2021 08 05.
Article in English | MEDLINE | ID: covidwho-1272172

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection continues to be a global health problem. Despite the current implementation of COVID-19 vaccination schedules, identifying effective antiviral drug treatments for this disease continues to be a priority. A recent study showed that masitinib (MST), a tyrosine kinase inhibitor, blocks the proteolytic activity of SARS-CoV-2 main protease (Mpro ). Although MST is a potential candidate for COVID-19 treatment, a comprehensive analysis of its interaction with Mpro has not been done. In this work, we performed molecular dynamics simulations of the MST-Mpro complex crystal structure. The effect of the protonation states of Mpro H163 residue and MST titratable groups were studied. Furthermore, we identified the MST substituents and Mpro mutations that affect the stability of the complex. Our results provide valuable insights into the design of new MST analogs as potential treatments for COVID-19.


Subject(s)
Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , SARS-CoV-2/enzymology , Thiazoles/metabolism , Benzamides , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Cysteine Proteinase Inhibitors/chemistry , Hydrogen Bonding , Molecular Dynamics Simulation , Mutation , Piperidines , Protein Binding , Pyridines , Static Electricity , Thiazoles/chemistry
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