scholarly journals A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium

2021 ◽  
Author(s):  
Jim Warwicker
Keyword(s):  
Linoleic Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Cell Surface ◽  
Ph Dependence ◽  
Salt Bridge ◽  
Spike Protein ◽  
Salt Bridges ◽  
Heat Map ◽  
Closed Conformation ◽  
Human Coronaviruses

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.

scholarly journals A model for pH coupling of the SARS-CoV-2 spike protein open/closed equilibrium

2020 ◽  
Author(s):  
Jim Warwicker
Keyword(s):  
Cell Surface ◽  
Aspartic Acid ◽  
Receptor Binding ◽  
Ph Dependence ◽  
Salt Bridge ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Salt Bridges ◽  
Heat Map ◽  
Human Coronaviruses

AbstractSARS-CoV-2, causative agent of the 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, 3 histidine residues in S2 are consistently predicted as destabilising in pre-fusion (all 3) and post-fusion (2 of 3) 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 have pKas that are calculated to be elevated and destabilising. Notably, the degree of destabilisation is predicted to vary between open and closed receptor binding domain conformations. It is therefore suggested that these groups contribute to a pH-dependence of the open/closed equilibrium. These observations are discussed in the context of SARS-CoV-2 infection, mutagenesis studies, and other human coronaviruses.

scholarly journals Immunological imprinting of the antibody response in COVID-19 patients

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Teresa Aydillo ◽  
Alexander Rombauts ◽  
Daniel Stadlbauer ◽  
Sadaf Aslam ◽  
Gabriela Abelenda-Alonso ◽  
...  
Keyword(s):  
Immune Response ◽  
Severe Acute Respiratory Syndrome ◽  
Antibody Response ◽  
Humoral Immune Response ◽  
Nucleocapsid Protein ◽  
Spike Protein ◽  
Ongoing Research ◽  
Variable Regions ◽  
Humoral Immune ◽  
Human Coronaviruses

AbstractIn addition to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), humans are also susceptible to six other coronaviruses, for which consecutive exposures to antigenically related and divergent seasonal coronaviruses are frequent. Despite the prevalence of COVID-19 pandemic and ongoing research, the nature of the antibody response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here we longitudinally profile the early humoral immune response against SARS-CoV-2 in hospitalized coronavirus disease 2019 (COVID-19) patients and quantify levels of pre-existing immunity to OC43, HKU1 and 229E seasonal coronaviruses, and find a strong back-boosting effect to conserved but not variable regions of OC43 and HKU1 betacoronaviruses spike protein. However, such antibody memory boost to human coronaviruses negatively correlates with the induction of IgG and IgM against SARS-CoV-2 spike and nucleocapsid protein. Our findings thus provide evidence of immunological imprinting by previous seasonal coronavirus infections that can potentially modulate the antibody profile to SARS-CoV-2 infection.

Metalloproteinase-dependent and TMPRSS2-independnt cell surface entry pathway of SARS-CoV-2 requires the furin-cleavage site and the S2 domain of spike protein

2021 ◽  
Author(s):  
Mizuki Yamamoto ◽  
Jin Gohda ◽  
Ayako Kobayashi ◽  
Keiko Tomita ◽  
Youko Hirayama ◽  
...  
Keyword(s):  
Cell Surface ◽  
Spike Protein ◽  
Dependent Manner ◽  
Furin Cleavage ◽  
Entry Pathway ◽  
Furin Cleavage Site ◽  
Metalloproteinase Inhibitors ◽  
A Cell ◽  
A Disintegrin And Metalloproteinase ◽  
Human Coronaviruses

The ongoing global vaccination program to prevent SARS-CoV-2 infection, the causative agent of COVID-19, has had significant success. However, recently virus variants have emerged that can evade the immunity in a host achieved through vaccination. Consequently, new therapeutic agents that can efficiently prevent infection from these new variants, and hence COVID-19 spread are urgently required. To achieve this, extensive characterization of virus-host cell interactions to identify effective therapeutic targets is warranted. Here, we report a cell surface entry pathway of SARS-CoV-2 that exists in a cell type-dependent manner is TMPRSS2-independent but sensitive to various broad-spectrum metalloproteinase inhibitors such as marimastat and prinomastat. Experiments with selective metalloproteinase inhibitors and gene-specific siRNAs revealed that a disintegrin and metalloproteinase 10 (ADAM10) is partially involved in the metalloproteinase pathway. Consistent with our finding that the pathway is unique to SARS-CoV-2 among highly pathogenic human coronaviruses, both the furin cleavage motif in the S1/S2 boundary and the S2 domain of SARS-CoV-2 spike protein are essential for metalloproteinase-dependent entry. In contrast, the two elements of SARS-CoV-2 independently contributed to TMPRSS2-dependent S2 priming. The metalloproteinase pathway is involved in SARS-CoV-2-induced syncytia formation and cytopathicity, leading us to theorize that it is also involved in the rapid spread of SARS-CoV-2 and the pathogenesis of COVID-19. Thus, targeting the metalloproteinase pathway in addition to the TMPRSS2 and endosome pathways could be an effective strategy by which to cure COVID-19 in the future.

scholarly journals Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63

2009 ◽  
Vol 84 (2) ◽  
pp. 1198-1205 ◽  
Author(s):  
Ilona Glowacka ◽  
Stephanie Bertram ◽  
Petra Herzog ◽  
Susanne Pfefferle ◽  
Imke Steffen ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Lung Injury ◽  
Vero Cells ◽  
Cell Entry ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Human Coronavirus ◽  
Angiotensin Converting Enzyme 2 ◽  
Similar Activity ◽  
Human Coronaviruses

ABSTRACT The human coronaviruses (CoVs) severe acute respiratory syndrome (SARS)-CoV and NL63 employ angiotensin-converting enzyme 2 (ACE2) for cell entry. It was shown that recombinant SARS-CoV spike protein (SARS-S) downregulates ACE2 expression and thereby promotes lung injury. Whether NL63-S exerts a similar activity is yet unknown. We found that recombinant SARS-S bound to ACE2 and induced ACE2 shedding with higher efficiency than NL63-S. Shedding most likely accounted for the previously observed ACE2 downregulation but was dispensable for viral replication. Finally, SARS-CoV but not NL63 replicated efficiently in ACE2-positive Vero cells and reduced ACE2 expression, indicating robust receptor interference in the context of SARS-CoV but not NL63 infection.

scholarly journals In Silico Study of Polyunsaturated Fatty Acids as Potential SARS-CoV-2 Spike Protein Closed Conformation Stabilizers: Epidemiological and Computational Approaches

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 711
Author(s):  
Alonso Vivar-Sierra ◽  
María José Araiza-Macías ◽  
José Patricio Hernández-Contreras ◽  
Arely Vergara-Castañeda ◽  
Gabriela Ramírez-Vélez ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
In Silico ◽  
Cell Types ◽  
Host Cells ◽  
Spike Protein ◽  
Omega 3 ◽  
Angiotensin Converting Enzyme 2 ◽  
Closed Conformation ◽  
In Silico Study ◽  
Omega 6

SARS-CoV-2 infects host cells by interacting its spike protein with surface angiotensin-converting enzyme 2 (ACE2) receptors, expressed in lung and other cell types. Although several risk factors could explain why some countries have lower incidence and fatality rates than others, environmental factors such as diet should be considered. It has been described that countries with high polyunsaturated fatty acid (PUFA) intake have a lower number of COVID-19 victims and a higher rate of recovery from the disease. Moreover, it was found that linoleic acid, an omega-6 PUFA, could stabilize the spike protein in a closed conformation, blocking its interaction with ACE2. These facts prompted us to perform in silico simulations to determine if other PUFA could also stabilize the closed conformation of spike protein and potentially lead to a reduction in SARS-CoV-2 infection. We found that: (a) countries whose source of omega-3 is from marine origin have lower fatality rates; and (b) like linoleic acid, omega-3 PUFA could also bind to the closed conformation of spike protein and therefore, could help reduce COVID-19 complications by reducing viral entrance to cells, in addition to their known anti-inflammatory effects.

scholarly journals Basic Coronavirus biology and vaccines for COVID-19

2021 ◽  
Vol 39 (4) ◽  
Author(s):  
Hernan Garcia-Ruiz ◽  
Katherine LaTourrette ◽  
Mayra Teresa Garcia-Ruiz
Keyword(s):  
Middle East ◽  
Severe Acute Respiratory Syndrome ◽  
Diagnostic Test ◽  
Drug Administration ◽  
Diagnostic Tests ◽  
Protein S ◽  
Antiviral Drugs ◽  
Genomic Variation ◽  
Spike Protein ◽  
Human Coronaviruses

<p><em>Severe acute respiratory syndrome coronavirus 2</em> (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. Two mRNA vaccines based on the spike protein S have been authorized by the Food and Drug Administration. Antibody-based diagnostic test detect antibodies developed against protein S. Mutations in the genome of SARS-CoV-2 might compromise the precision of diagnostic tests and the efficacy of vaccines and antiviral drugs. We recently profiled genomic variation in human coronaviruses SARS[1]CoV, SARS-CoV-2, and <em>Middle East respiratory syndrome coronavirus</em> (MERS-CoV). As in all species of the genus Betacoronavirus, the genome is hyper variable, and mutations are not random. The most variable cistron codes for the spike S protein. Hyper variation in protein S has the potential to affect the efficacy of vaccines, the reliability of antibody-based diagnostic test, and predicts potential for repeated SARS-CoV-2 infections. Here we review the basics of coronavirus biology and genomic variation, and link them to diagnostic tests, vaccines, and antiviral drugs.</p>

scholarly journals Structural Identification of the Electrostatic Hot Spots for Severe Acute Respiratory Syndrome Coronavirus Spike Protein to Be Complexed with Its Receptor ACE2 and Its Neutralizing Antibodies

2020 ◽  
Author(s):  
Wei Li
Keyword(s):  
Hot Spots ◽  
Neutralizing Antibodies ◽  
Complex Structure ◽  
Salt Bridge ◽  
Spike Protein ◽  
The Novel ◽  
Salt Bridges ◽  
Angiotensin Converting Enzyme 2 ◽  
Receptor Recognition ◽  
Novel Coronavirus

The spike protein of SARS coronavirus (SARS-CoV) attaches the virus to its cellular receptor, angiotensin-converting enzyme 2 (ACE2), which is mediated by the receptor binding domain (RBD) of the spike protein. Recently, an analysis based on decade-long structural studies of SARS was reported to illustrate with atomic-level details receptor recognition by the novel coronavirus from Wuhan, i.e., 2019-nCoV. Here, this article reports a comprehensive set of structural electrostatic analysis of all SARS-CoV spike protein RBD-related structures as of February 13, 2020, aiming at identifying the electrostatic hot spots for SARS-CoV spike protein to be complexed with ACE2 and its neutralizing antibodies. First, this article identified a structural action mechanism of the F26G19 antibody (of SARS-CoV spike protein), where its Asp56 residue binds to the Arg426 of the SARS-CoV spike protein RBD against the formation of the interfacial Arg426-Glu329 salt bridges between ACE2 and the SARS-CoV spike protein RBD. Second, a hypothesis is reported that a pair of electrostatic clips exist at the interface between ACE2 and the SARS-CoV spike protein RBD, including both Arg426-Glu329 and His445-Glu23-Lys447 salt bridges. Last, this article reports a structurally identified interfacial Glu35-Arg479 salt bridge which helps stabilize the complex structure of ACE2 and the SARS-CoV spike protein RBD. Overall, the structurally identified electrostatic hot spots reported here may be useful for the design of SARS-CoV-neutralizing antibodies in future.

Salt bridges in model peptides

1988 ◽  
Vol 53 (11) ◽  
pp. 2810-2824 ◽  
Author(s):  
Ilmars Sekacis ◽  
Mark Shenderovich ◽  
Gregory Nikiforovich ◽  
Edvards Liepinš ◽  
Ludmila Polevaya ◽  
...  
Keyword(s):  
Synthetic Peptides ◽  
Salt Bridge ◽  
Peptide Bond ◽  
Space Structure ◽  
Side Chain ◽  
Amino Group ◽  
Salt Bridges ◽  
Ionic Bond ◽  
Theoretical Conformational Analysis ◽  
H Nmr

A group of synthetic peptides including Boc-Lys-Phe-X-Y, X = Ala (I, III) or Thr (II), Y = Pro (I, II) or Ala (III) was studied by means of 1H NMR spectroscopy and theoretical conformational analysis. Compound I in DMSO shows two conformers with the trans- and cis-configuration of the peptide bond Ala-Pro. The salt bridge between the Lys ε-amino group and the C-terminal carboxyl is featured by magnetic nonequivalence of the Lys CεH2 protons. The space structure of I and II was found to possess a salt bridge fixed by an unusual turn in the chain formed by the Lys side chain and the C-terminal dipeptide with the trans-peptide bond X-Pro. Since a stable ionic bond in III and in the cis-conformer of I has not been observed, its contribution to stabilization of the space structure of the peptides in DMSO appears rather small.

scholarly journals Replication, pathogenicity, and transmission of SARS-CoV-2 in minks

2020 ◽  
Author(s):  
Lei Shuai ◽  
Gongxun Zhong ◽  
Quan Yuan ◽  
Zhiyuan Wen ◽  
Chong Wang ◽  
...  
Keyword(s):  
Animal Model ◽  
Severe Acute Respiratory Syndrome ◽  
Subunit Vaccine ◽  
Lung Damage ◽  
Spike Protein ◽  
Pulmonary Lesions ◽  
Potential Strategy ◽  
Respiratory Droplets

Abstract Minks are raised in many countries and have transmitted severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) to humans. However, the biologic properties of SARS-CoV-2 in minks are largely unknown. Here, we investigated and found that SARS-CoV-2 replicates efficiently in both the upper and lower respiratory tracts, and transmits efficiently in minks via respiratory droplets; pulmonary lesions caused by SARS-CoV-2 in minks are similar to those seen in humans with COVID-19. We further found that a spike protein-based subunit vaccine largely prevented SARS-CoV-2 replication and lung damage caused by SARS-CoV-2 infection in minks. Our study indicates that minks are a useful animal model for evaluating the efficacy of drugs or vaccines against COVID-19 and that vaccination is a potential strategy to prevent minks from transmitting SARS-CoV-2.

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