scholarly journals Molecular basis of the potential interaction of SARS-CoV-2 spike protein to CD147 in COVID-19 associated-lymphopenia

2020 ◽  
pp. 1-11 ◽  
Author(s):  
Mohamed A. Helal ◽  
Shaimaa Shouman ◽  
Ahmad Abdelwaly ◽  
Ahmed O. Elmehrath ◽  
Mohamed Essawy ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Potential Interaction ◽  
Spike Protein

scholarly journals Strong evolutionary convergence of receptor-binding protein spike between COVID-19 and SARS-related coronaviruses

2020 ◽  
Author(s):  
Yonghua Wu
Keyword(s):  
Receptor Binding ◽  
Molecular Basis ◽  
Acid Sites ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Partner Protein ◽  
Evolutionary Convergence ◽  
Genome Level ◽  
Phenotypic Convergence

AbstractCoronavirus Disease 2019 (COVID-19) and severe acute respiratory syndrome (SARS)-related coronaviruses (e.g., 2019-nCoV and SARS-CoV) are phylogenetically distantly related, but both are capable of infecting human hosts via the same receptor, angiotensin-converting enzyme 2, and cause similar clinical and pathological features, suggesting their phenotypic convergence. Yet, the molecular basis that underlies their phenotypic convergence remains unknown. Here, we used a recently developed molecular phyloecological approach to examine the molecular basis leading to their phenotypic convergence. Our genome-level analyses show that the spike protein, which is responsible for receptor binding, has undergone significant Darwinian selection along the branches related to 2019-nCoV and SARS-CoV. Further examination shows an unusually high proportion of evolutionary convergent amino acid sites in the receptor binding domain (RBD) of the spike protein between COVID-19 and SARS-related CoV clades, leading to the phylogenetic uniting of their RBD protein sequences. In addition to the spike protein, we also find the evolutionary convergence of its partner protein, ORF3a, suggesting their possible co-evolutionary convergence. Our results demonstrate a strong adaptive evolutionary convergence between COVID-19 and SARS-related CoV, possibly facilitating their adaptation to similar or identical receptors. Finally, it should be noted that many observed bat SARS-like CoVs that have an evolutionary convergent RBD sequence with 2019-nCoV and SARS-CoV may be pre-adapted to human host receptor ACE2, and hence would be potential new coronavirus sources to infect humans in the future.

scholarly journals SARS-CoV-2 variants resist antibody neutralization and broaden host ACE2 usage

2021 ◽  
Author(s):  
Ruoke Wang ◽  
Qi Zhang ◽  
Jiwan Ge ◽  
Wenlin Ren ◽  
Rui Zhang ◽  
...  
Keyword(s):  
South Africa ◽  
Monoclonal Antibodies ◽  
Molecular Basis ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Antibody Neutralization ◽  
Vaccine Protection ◽  
Antigenic Sites ◽  
Global Pandemic ◽  
Crystal Structural

AbstractNew SARS-CoV-2 variants continue to emerge from the current global pandemic, some of which can replicate faster and with greater transmissibility and pathogenicity. In particular, UK501Y.V1 identified in UK, SA501Y.V2 in South Africa, and BR501Y.V3 in Brazil are raising serious concerns as they spread quickly and contain spike protein mutations that may facilitate escape from current antibody therapies and vaccine protection. Here, we constructed a panel of 28 SARS-CoV-2 pseudoviruses bearing single or combined mutations found in the spike protein of these three variants, as well as additional nine mutations that within or close by the major antigenic sites in the spike protein identified in the GISAID database. These pseudoviruses were tested against a panel of monoclonal antibodies (mAbs), including some approved for emergency use to treat SARS-CoV-2 infection, and convalescent patient plasma collected early in the pandemic. SA501Y.V2 pseudovirus was the most resistant, in magnitude and breadth, against mAbs and convalescent plasma, followed by BR501Y.V3, and then UK501Y.V1. This resistance hierarchy corresponds with Y144del and 242-244del mutations in the N-terminal domain as well as K417N/T, E484K and N501Y mutations in the receptor binding domain (RBD). Crystal structural analysis of RBD carrying triple K417N-E484K-N501Y mutations found in SA501Y.V2 bound with mAb P2C-1F11 revealed a molecular basis for antibody neutralization and escape. SA501Y.V2 and BR501Y.V3 also acquired substantial ability to use mouse and mink ACE2 for entry. Taken together, our results clearly demonstrate major antigenic shifts and potentially broadening the host range of SA501Y.V2 and BR501Y.V3, which pose serious challenges to our current antibody therapies and vaccine protection.

scholarly journals Molecular basis for SARS-CoV-2 spike affinity for human ACE2 receptor

2020 ◽  
Author(s):  
Julián M. Delgado ◽  
Nalvi Duro ◽  
David M. Rogers ◽  
Alexandre Tkatchenko ◽  
Sagar A. Pandit ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Basis ◽  
Free Energy Calculations ◽  
Spike Protein ◽  
Salt Bridges ◽  
Recognition Mechanism ◽  
X Ray ◽  
Receptor Recognition ◽  
Structural Fluctuations ◽  
Dynamics Simulations

AbstractSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused substantially more infections, deaths, and economic disruptions than the 2002-2003 SARS-CoV. The key to understanding SARS-CoV-2’s higher infectivity may lie in its host receptor recognition mechanism. This is because experiments show that the human ACE2 protein, which serves as the primary receptor for both CoVs, binds to CoV-2’s spike protein 5-20 fold stronger than SARS-CoV’s spike protein. The molecular basis for this difference in binding affinity, however, remains unexplained and, in fact, a comparison of X-ray structures leads to an opposite proposition. To gain insight, we use all-atom molecular dynamics simulations. Free energy calculations indicate that CoV-2’s higher affinity is due primarily to differences in specific spike residues that are local to the spike-ACE2 interface, although there are allosteric effects in binding. Comparative analysis of equilibrium simulations reveals that while both CoV and CoV-2 spike-ACE2 complexes have similar interfacial topologies, CoV-2’s spike protein engages in greater numbers, combinatorics and probabilities of hydrogen bonds and salt bridges with ACE2. We attribute CoV-2’s higher affinity to these differences in polar contacts, and these findings also highlight the importance of thermal structural fluctuations in spike-ACE2 complexation. We anticipate that these findings will also inform the design of spike-ACE2 peptide blockers that, like in the cases of HIV and Influenza, can serve as antivirals.

scholarly journals Scanning the RBD-ACE2 molecular interactions in Omicron variant

2021 ◽  
Author(s):  
Soumya Lipsa Rath ◽  
Aditya Kumar Padhi ◽  
Nabanita Mandal
Keyword(s):  
Molecular Basis ◽  
Human Population ◽  
Direct Interaction ◽  
Spike Protein ◽  
Amino Acid Substitutions ◽  
Receptor Complex ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Charge Dynamics ◽  
Dynamics Simulations

The emergence of new SARS-CoV-2 variants poses a threat to the human population where it is difficult to assess the severity of a particular variant of the virus. Spike protein and specifically its receptor binding domain (RBD) which makes direct interaction with the ACE2 receptor of the human has shown prominent amino acid substitutions in most of the Variants of Concern. Here, by using all-atom molecular dynamics simulations we compare the interaction of Wild-type RBD/ACE2 receptor complex with that of the latest Omicron variant of the virus. We observed a very interesting diversification of the charge, dynamics and energetics of the protein complex formed upon mutations. These results would help us in understanding the molecular basis of binding of the Omicron variant with that of SARS-CoV-2 Wild-type.

scholarly journals Molecular basis of the logical evolution of the novel coronavirus SARS-CoV-2: A comparative analysis

2020 ◽  
Author(s):  
Abhisek Dwivedy ◽  
Krushna Chandra Murmu ◽  
Mohammed Ahmad ◽  
Punit Prasad ◽  
Bichitra Kumar Biswal ◽  
...  
Keyword(s):  
Molecular Basis ◽  
Conformational Flexibility ◽  
Spike Protein ◽  
The Novel ◽  
Amino Acid Residues ◽  
Evolutionary Pathway ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Coronaviruses ◽  
Novel Coronavirus ◽  
Current Report

AbstractA novel disease, COVID-19, is sweeping the world since end of 2019. While in many countries, the first wave is over, but the pandemic is going through its next phase with a significantly higher infectability. COVID-19 is caused by the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that seems to be more infectious than any other previous human coronaviruses. To understand any unique traits of the virus that facilitate its entry into the host, we compared the published structures of the viral spike protein of SARS-CoV-2 with other known coronaviruses to determine the possible evolutionary pathway leading to the higher infectivity. The current report presents unique information regarding the amino acid residues that were a) conserved to maintain the binding with ACE2 (Angiotensin-converting enzyme 2), and b) substituted to confer an enhanced binding affinity and conformational flexibility to the SARS-CoV-2 spike protein. The present study provides novel insights into the evolutionary nature and molecular basis of higher infectability and perhaps the virulence of SARS-CoV-2.

scholarly journals A potential interaction between the SARS-CoV-2 spike protein and nicotinic acetylcholine receptors

2021 ◽  
Vol 120 (6) ◽  
pp. 983-993 ◽  
Author(s):  
A. Sofia F. Oliveira ◽  
Amaurys Avila Ibarra ◽  
Isabel Bermudez ◽  
Lorenzo Casalino ◽  
Zied Gaieb ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Potential Interaction ◽  
Spike Protein ◽  
Nicotinic Acetylcholine

scholarly journals Repurposing of Approved Drugs with Potential to Block SARS-CoV-2 Surface Glycoprotein Interaction with Host Receptor

2020 ◽  
Author(s):  
Abu Sajib
Keyword(s):  
In Silico ◽  
Potential Interaction ◽  
Surface Glycoprotein ◽  
Spike Protein ◽  
Striking Similarity ◽  
Spike Glycoprotein ◽  
Human Lung Epithelial Cell ◽  
Angiotensin I Converting Enzyme ◽  
Human Lungs ◽  
Approved Drugs

Background: Respiratory transmission is the primary route of SARS-CoV-2 infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 spike glycoprotein for entry into human cells. A recent study reported absent to low ACE2 promoter activity in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE in human lungs compared to very low expression of ACE2. Methods: In silico tools were applied to assess potential interaction of SARS-CoV-2 surface spike protein with human ACE as well as predict the drugs that may block SARS-CoV-2 interaction with host receptor. Results: Although it is not obvious from the primary sequence alignment of ACE2 and its homolog ACE (also known as ACE1), comparison of X-ray crystallographic structures show striking similarity in the regions of these proteins which is known (for ACE2) to interact with the receptor binding domain (RBD) of SARS-CoV-2 spike protein. Critical amino acids that mediate interaction with the viral spike protein in ACE2 are organized in the same order in ACE. In silico analyses predicts comparable interaction of SARS-CoV-2 spike protein with ACE2 and ACE. In addition, this study predicts and selects already approved drugs from a list of 1263, which may interfere with the binding of SARS-CoV-2 spike glycoprotein to ACE2 and/or ACE.

scholarly journals Unraveling the molecular basis of host cell receptor usage in SARS-CoV-2 and other human pathogenic β-CoVs

2020 ◽  
Author(s):  
Camila Pontes ◽  
Victoria Ruiz-Serra ◽  
Rosalba Lepore ◽  
Alfonso Valencia
Keyword(s):  
Host Cell ◽  
Molecular Basis ◽  
Human Population ◽  
Cell Receptor ◽  
Protein Family ◽  
Spike Protein ◽  
Receptor Usage ◽  
Host Cell Receptor ◽  
Unsupervised Analysis ◽  
Conservation Patterns

AbstractThe recent emergence of the novel SARS-CoV-2 in China and its rapid spread in the human population has led to a public health crisis worldwide. Like in SARS-CoV, horseshoe bats currently represent the most likely candidate animal source for SARS-CoV-2. Yet, the specific mechanisms of cross-species transmission and adaptation to the human host remain unknown. Here we show that the unsupervised analysis of conservation patterns across the β-CoV spike protein family, using sequence information alone, can provide rich information on the molecular basis of the specificity of β-CoVs to different host cell receptors. More precisely, our results indicate that host cell receptor usage is encoded in the amino acid sequences of different CoV spike proteins in the form of a set of specificity determining positions (SDPs). Furthermore, by integrating structural data, in silico mutagenesis and coevolution analysis we could elucidate the role of SDPs in mediating ACE2 binding across the Sarbecovirus lineage, either by engaging the receptor through direct intermolecular interactions or by affecting the local environment of the receptor binding motif. Finally, by the analysis of coevolving mutations across a paired MSA we were able to identify key intermolecular contacts occurring at the spike-ACE2 interface. These results show that effective mining of the evolutionary records held in the sequence of the spike protein family can help tracing the molecular mechanisms behind the evolution and host-receptors adaptation of circulating and future novel β-CoVs.SignificanceUnraveling the molecular basis for host cell receptor usage among β-CoVs is crucial to our understanding of cross-species transmission, adaptation and for molecular-guided epidemiological monitoring of potential outbreaks. In the present study, we survey the sequence conservation patterns of the β-CoV spike protein family to identify the evolutionary constraints shaping the functional specificity of the protein across the β-CoV lineage. We show that the unsupervised analysis of statistical patterns in a MSA of the spike protein family can help tracing the amino acid space encoding the specificity of β-CoVs to their cognate host cell receptors. We argue that the results obtained in this work can provide a framework for monitoring the evolution of SARS-CoV-2 specificity to the hACE2 receptor, as the virus continues spreading in the human population and differential virulence starts to arise.

scholarly journals Structural and functional analysis of female sex hormones against SARS-Cov2 cell entry

2020 ◽  
Author(s):  
Jorge Alberto Aguilar-Pineda ◽  
Mazen Albaghdadi ◽  
Wanlin Jiang ◽  
Karin J. Vera Lopez ◽  
Gonzalo Davila Del-Carpio ◽  
...  
Keyword(s):  
Sex Hormones ◽  
Protein Interactions ◽  
Molecular Basis ◽  
Severe Infection ◽  
Cell Entry ◽  
Spike Protein ◽  
Female Sex ◽  
Female Sex Hormones ◽  
Shed Light ◽  
Putative Mechanism

AbstractEmerging evidence suggests that males are more susceptible to severe infection by the SARS-CoV-2 virus than females. A variety of mechanisms may underlie the observed gender-related disparities including differences in sex hormones. However, the precise mechanisms by which female sex hormones may provide protection against SARS-CoV-2 infectivity remains unknown. Here we report new insights into the molecular basis of the interactions between the SARS-CoV-2 spike (S) protein and the human ACE2 receptor. We further observed that glycosylation of the ACE2 receptor enhances SARS-CoV-2 infectivity. Importantly estrogens can disrupt glycan-glycan interactions and glycan-protein interactions between the human ACE2 and the SARS-CoV2 thereby blocking its entry into cells. In a mouse model, estrogens reduced ACE2 glycosylation and thereby alveolar uptake of the SARS-CoV-2 spike protein. These results shed light on a putative mechanism whereby female sex hormones may provide protection from developing severe infection and could inform the development of future therapies against COVID-19.

Sign in / Sign up

Export Citation Format

Share Document