scholarly journals Phospholipids dock SARS-CoV-2 spike protein via hydrophobic interactions: a minimal in-silico study of lecithin nasal spray therapy

2021 ◽  
Author(s):  
Muhammad Nawaz Qaisrani ◽  
Jawad Ur Rehman ◽  
Roman Belousov ◽  
Elham Moharramzadeh Goliaei ◽  
Ivan Girotto ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Viral Infections ◽  
Hydrophobic Interactions ◽  
Chemical Properties ◽  
Binding Energies ◽  
Spike Protein ◽  
Binding Motif ◽  
Binding Domains ◽  
Preferential Binding ◽  
Dynamics Simulations

<div><div><div><p>Understanding the physical and chemical properties of viral infections at molecular scales is a major challenge for the scientific community more so with the outbreak of global pandemics. There is currently a lot of effort being placed in identifying molecules that could act as putative drugs or blockers of viral molecules. In this work, we computationally explore the importance in antiviral activity of a less studied class of molecules, namely surfactants. We employ all-atoms molecular dynamics simulations to study the interaction between the receptor-binding domain of the SARS-CoV-2 spike protein and the phospholipid lecithin (POPC), in water. Our microsecond simulations show a preferential binding of lecithin to the receptor-binding motif of SARS-CoV-2 with binding energies significantly larger than kBT. Furthermore, hydrophobic interactions in- volving lecithin non-polar tails dominate these binding events, which are also accompanied by dewetting of the receptor binding motif. Through an analysis of fluctuations in the radius of gyra- tion of the receptor-binding domains, its contact maps with lecithin molecules, and distributions of water molecules near the binding region, we elucidate molecular interactions that may play an important role in interactions involving surfactant-type molecules and viruses. We discuss our minimal computational model in the context of lecithin-based liposomal nasal sprays as putative mitigating therapies for COVID-19.</p></div></div></div>

scholarly journals Lecithin as a Putative Biodegradable Blocker of SARS-CoV-2

2020 ◽  
Author(s):  
Muhammad Nawaz Qaisrani ◽  
Jawad Ur Rehman ◽  
Roman Belousov ◽  
Elham Moharramzadeh Goliaei ◽  
Ivan Girotto ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Hydrophobic Interactions ◽  
Chemical Properties ◽  
Binding Motif ◽  
Proof Of Concept ◽  
Angiotensin Converting Enzyme 2 ◽  
Preferential Binding ◽  
Dynamics Simulations ◽  
Physical And Chemical ◽  
And Chemical Properties

<p>Understanding the physical and chemical properties of viral infection at molecular scales is a major challenge of the scientific community in the fight against the Coronavirus (COVID-19) pandemic. We employ all-atoms molecular dynamics simulations to study the interaction between the receptor-binding domain of the SARS-CoV-2 spike protein and the surfactant lecithin in water solutions. Our microsecond simulations reveal a preferential binding of lecithin to the receptor-binding motif (RBM) of SARS-CoV-2. Furthermore, we find that the lecitin-RBM binding events are mainly dominated by the hydrophobic interactions, which are accompanied by dewetting of water molecules near the RBM. These proof-of-concept simulations provide a demonstration of the use of biodegradable phospholipids as blockers of binding of SARS-CoV-2 with the human Angiotensin-Converting Enzyme 2 (ACE2) receptor.</p>

scholarly journals Lecithin as a Putative Biodegradable Blocker of SARS-CoV-2

2020 ◽  
Author(s):  
Muhammad Nawaz Qaisrani ◽  
Jawad Ur Rehman ◽  
Roman Belousov ◽  
Elham Moharramzadeh Goliaei ◽  
Ivan Girotto ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Hydrophobic Interactions ◽  
Chemical Properties ◽  
Binding Motif ◽  
Proof Of Concept ◽  
Angiotensin Converting Enzyme 2 ◽  
Preferential Binding ◽  
Dynamics Simulations ◽  
Physical And Chemical ◽  
And Chemical Properties

<p>Understanding the physical and chemical properties of viral infection at molecular scales is a major challenge of the scientific community in the fight against the Coronavirus (COVID-19) pandemic. We employ all-atoms molecular dynamics simulations to study the interaction between the receptor-binding domain of the SARS-CoV-2 spike protein and the surfactant lecithin in water solutions. Our microsecond simulations reveal a preferential binding of lecithin to the receptor-binding motif (RBM) of SARS-CoV-2. Furthermore, we find that the lecitin-RBM binding events are mainly dominated by the hydrophobic interactions, which are accompanied by dewetting of water molecules near the RBM. These proof-of-concept simulations provide a demonstration of the use of biodegradable phospholipids as blockers of binding of SARS-CoV-2 with the human Angiotensin-Converting Enzyme 2 (ACE2) receptor.</p>

scholarly journals Lecithin as a Putative Biodegradable Blocker of SARS-CoV-2

2020 ◽  
Author(s):  
Muhammad Nawaz Qaisrani ◽  
Jawad Ur Rehman ◽  
Roman Belousov ◽  
Elham Moharramzadeh Goliaei ◽  
Ivan Girotto ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Hydrophobic Interactions ◽  
Chemical Properties ◽  
Binding Motif ◽  
Proof Of Concept ◽  
Angiotensin Converting Enzyme 2 ◽  
Preferential Binding ◽  
Dynamics Simulations ◽  
Physical And Chemical ◽  
And Chemical Properties

<p>Understanding the physical and chemical properties of viral infection at molecular scales is a major challenge of the scientific community in the fight against the Coronavirus (COVID-19) pandemic. We employ all-atoms molecular dynamics simulations to study the interaction between the receptor-binding domain of the SARS-CoV-2 spike protein and the surfactant lecithin in water solutions. Our microsecond simulations reveal a preferential binding of lecithin to the receptor-binding motif (RBM) of SARS-CoV-2. Furthermore, we find that the lecitin-RBM binding events are mainly dominated by the hydrophobic interactions, which are accompanied by dewetting of water molecules near the RBM. These proof-of-concept simulations provide a demonstration of the use of biodegradable phospholipids as blockers of binding of SARS-CoV-2 with the human Angiotensin-Converting Enzyme 2 (ACE2) receptor.</p>

scholarly journals Computer Simulations of the interaction between SARS-CoV-2 spike glycoprotein and different surfaces

2020 ◽  
Author(s):  
David C. Malaspina ◽  
Jordi Faraudo
Keyword(s):  
Molecular Dynamics ◽  
Hydrogen Bonding ◽  
Receptor Binding ◽  
Hydrophobic Interactions ◽  
Prominent Feature ◽  
High Hydrogen ◽  
Binding Domains ◽  
Dynamics Simulations ◽  
Initial Adsorption ◽  
Binding Subunit

A prominent feature of coronaviruses is the presence of a large glycoprotein spike protruding from a lipidic membrane. This glycoprotein spike determines the interaction of coronaviruses with the environment and the host. In this paper, we perform all atomic Molecular Dynamics simulations of the interaction between the SARS-CoV-2 trimeric glycoprotein spike and surfaces of materials. We considered a material with high hydrogen bonding capacity (cellulose) and a material capable of strong hydrophobic interactions (graphite). Initially, the spike adsorbs to both surfaces through essentially the same residues belonging to the receptor binding subunit of its three monomers. Adsorption onto cellulose stabilizes in this configuration, with the help of a large number of hydrogen bonds developed between cellulose and the three receptor binding domains (RBD) of the glycoprotein spike. In the case of adsorption onto graphite, the initial adsorption configuration is not stable and the surface induces a substantial deformation of the glycoprotein spike with a large number of adsorbed residues not pertaining to the binding subunits of the spike monomers.

scholarly journals Design of a companion bioinformatic tool to detect the emergence and geographical distribution of SARS-CoV-2 Spike protein genetic variants

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Alice Massacci ◽  
Eleonora Sperandio ◽  
Lorenzo D’Ambrosio ◽  
Mariano Maffei ◽  
Fabio Palombo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Consensus Sequence ◽  
Cell Epitope ◽  
Vaccine Design ◽  
Binding Domain ◽  
Spike Protein ◽  
Antibody Activity ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
The Impact

Abstract Background Tracking the genetic variability of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) is a crucial challenge. Mainly to identify target sequences in order to generate robust vaccines and neutralizing monoclonal antibodies, but also to track viral genetic temporal and geographic evolution and to mine for variants associated with reduced or increased disease severity. Several online tools and bioinformatic phylogenetic analyses have been released, but the main interest lies in the Spike protein, which is the pivotal element of current vaccine design, and in the Receptor Binding Domain, that accounts for most of the neutralizing the antibody activity. Methods Here, we present an open-source bioinformatic protocol, and a web portal focused on SARS-CoV-2 single mutations and minimal consensus sequence building as a companion vaccine design tool. Furthermore, we provide immunogenomic analyses to understand the impact of the most frequent RBD variations. Results Results on the whole GISAID sequence dataset at the time of the writing (October 2020) reveals an emerging mutation, S477N, located on the central part of the Spike protein Receptor Binding Domain, the Receptor Binding Motif. Immunogenomic analyses revealed some variation in mutated epitope MHC compatibility, T-cell recognition, and B-cell epitope probability for most frequent human HLAs. Conclusions This work provides a framework able to track down SARS-CoV-2 genomic variability.

Compared with SARS-CoV2 wild type's spike protein, the SARS-CoV2 omicron's receptor binding motif has adopted a more SARS-CoV1 and/or bat/civet-like structure.

2021 ◽  
Author(s):  
Michael O. Glocker ◽  
Kwabena F. M. Opuni ◽  
Hans-Juergen Thiesen
Keyword(s):  
Free Energy ◽  
Receptor Binding ◽  
Free Energy Calculations ◽  
Viral Fitness ◽  
Spike Protein ◽  
Receptor Protein ◽  
Binding Motif ◽  
Energy Calculations ◽  
Selection Processes ◽  
Protein Receptor

Our study focuses on free energy calculations of SARS-Cov2 spike protein receptor binding motives (RBMs) from wild type and variants-of-concern with particular emphasis on currently emerging SARS- CoV2 omicron variants of concern (VOC). Our computational free energy analysis underlines the occurrence of positive selection processes that specify omicron host adaption and bring changes on the molecular level into context with clinically relevant observations. Our free energy calculations studies regarding the interaction of omicron's RBM with human ACE2 shows weaker binding to ACE2 than alpha's, delta's, or wild type's RBM. Thus, less virus is predicted to be generated in time per infected cell. Our mutant analyses predict with focus on omicron variants a reduced spike-protein binding to ACE2--receptor protein possibly enhancing viral fitness / transmissibility and resulting in a delayed induction of danger signals as trade-off. Finally, more virus is produced but less per cell accompanied with delayed Covid-19 immunogenicity and pathogenicity. Regarding the latter, more virus is assumed to be required to initiate inflammatory immune responses.

scholarly journals Investigation of the effect of temperature on the structure of SARS-Cov-2 Spike Protein by Molecular Dynamics Simulations

2020 ◽  
Author(s):  
Soumya Lipsa Rath ◽  
Kishant Kumar
Keyword(s):  
Receptor Binding ◽  
Transmembrane Domain ◽  
Molecular Level ◽  
Spike Protein ◽  
Effect Of Temperature ◽  
Binding Motif ◽  
Structural Protein ◽  
Closed Conformation ◽  
Different Temperatures ◽  
Human Receptor

ABSTRACTStatistical and epidemiological data imply temperature sensitivity of the SARS-CoV-2 coronavirus. However, the molecular level understanding of the virus structure at different temperature is still not clear. Spike protein is the outermost structural protein of the SARS-CoV-2 virus which interacts with the Angiotensin Converting Enzyme 2 (ACE2), a human receptor, and enters the respiratory system. In this study, we performed an all atom molecular dynamics simulation to study the effect of temperature on the structure of the Spike protein. After 200ns of simulation at different temperatures, we came across some interesting phenomena exhibited by the protein. We found that the solvent exposed domain of Spike protein, namely S1, is more mobile than the transmembrane domain, S2. Structural studies implied the presence of several charged residues on the surface of N-terminal Domain of S1 which are optimally oriented at 10-30 °C. Bioinformatics analyses indicated that it is capable of binding to other human receptors and should not be disregarded. Additionally, we found that receptor binding motif (RBM), present on the receptor binding domain (RBD) of S1, begins to close around temperature of 40 °C and attains a completely closed conformation at 50 °C. The closed conformation disables its ability to bind to ACE2, due to the burying of its receptor binding residues. Our results clearly show that there are active and inactive states of the protein at different temperatures. This would not only prove beneficial for understanding the fundamental nature of the virus, but would be also useful in the development of vaccines and therapeutics.Graphical AbstractHighlightsStatistical and epidemiological evidence show that external climatic conditions influence the SARS-CoV infectivity, but we still lack a molecular level understanding of the same.Here, we study the influence of temperature on the structure of the Spike glycoprotein, the outermost structural protein, of the virus which binds to the human receptor ACE2.Results show that the Spike’s S1 domain is very sensitive to external atmospheric conditions compared to the S2 transmembrane domain.The N-terminal domain comprises of several solvent exposed charged residues that are capable of binding to human proteins. The region is specifically stable at temperatures ranging around 10-30° C.The Receptor Binding Motif adopts a closed conformation at 40°C and completely closes at higher temperatures making it unsuitable of binding to human receptors

scholarly journals Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

2021 ◽  
Author(s):  
Pengfei Wang ◽  
Manoj S. Nair ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk ◽  
Antibody Resistance

The COVID-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1–3, with more in the pipeline4–7. Furthermore, multiple vaccine constructs have shown promise8, including two with ~95% protective efficacy against COVID-199,10. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. The recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a few mAbs to the receptor-binding domain (RBD). It is not more resistant to convalescent plasma or vaccinee sera. Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals PfEMP1 A-Type ICAM-1-Binding Domains Are Not Associated with Cerebral Malaria in Beninese Children

mBio ◽  
2020 ◽  
Vol 11 (6) ◽  
Author(s):  
V. Joste ◽  
E. Guillochon ◽  
J. Fraering ◽  
B. Vianou ◽  
L. Watier ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Cerebral Malaria ◽  
Cell Lines ◽  
Receptor Binding ◽  
Binding Motif ◽  
Endothelial Protein C Receptor ◽  
Content Type ◽  
Binding Domains ◽  
Cerebrovascular Endothelium

ABSTRACT PfEMP1 is the major antigen involved in Plasmodium falciparum-infected erythrocyte sequestration in cerebrovascular endothelium. While some PfEMP1 domains have been associated with clinical phenotypes of malaria, formal associations between the expression of a specific domain and the adhesion properties of clinical isolates are limited. In this context, 73 cerebral malaria (CM) and 98 uncomplicated malaria (UM) Beninese children were recruited. We attempted to correlate the cytoadherence phenotype of Plasmodium falciparum isolates with the clinical presentation and the expression of specific PfEMP1 domains. Cytoadherence level on Hbec-5i and CHO-ICAM-1 cell lines and var genes expression were measured. We also investigated the prevalence of the ICAM-1-binding amino acid motif and dual receptor-binding domains, described as a potential determinant of cerebral malaria pathophysiology. We finally evaluated IgG levels against PfEMP1 recombinant domains (CIDRα1.4, DBLβ3, and CIDRα1.4-DBLβ3). CM isolates displayed higher cytoadherence levels on both cell lines, and we found a correlation between CIDRα1.4-DBLβ1/3 domain expression and CHO-ICAM-1 cytoadherence level. Endothelial protein C receptor (EPCR)-binding domains were overexpressed in CM isolates compared to UM whereas no difference was found in ICAM-1-binding DBLβ1/3 domain expression. Surprisingly, both CM and UM isolates expressed ICAM-1-binding motif and dual receptor-binding domains. There was no difference in IgG response against DBLβ3 between CM and UM isolates expressing ICAM-1-binding DBLβ1/3 domain. It raises questions about the role of this motif in CM pathophysiology, and further studies are needed, especially on the role of DBLβ1/3 without the ICAM-1-binding motif. IMPORTANCE Cerebral malaria pathophysiology remains unknown despite extensive research. PfEMP1 proteins have been identified as the main Plasmodium antigen involved in cerebrovascular endothelium sequestration, but it is unclear which var gene domain is involved in Plasmodium cytoadhesion. EPCR binding is a major determinant of cerebral malaria whereas the ICAM-1-binding role is still questioned. Our study confirmed the EPCR-binding role in CM pathophysiology with a major overexpression of EPCR-binding domains in CM isolates. In contrast, ICAM-1-binding involvement appears less obvious with A-type ICAM-1-binding and dual receptor-binding domain expression in both CM and UM isolates. We did not find any variations in ICAM-1-binding motif sequences in CM compared to UM isolates. UM and CM patients infected with isolates expressing the ICAM-1-binding motif displayed similar IgG levels against DBLβ3 recombinant protein. Our study raises interrogations about the role of these domains in CM physiopathology and questions their use in vaccine strategies against cerebral malaria.

Computational optimization of the SARS-CoV-2 receptor-binding-motif affinity for human ACE2

2020 ◽  
Author(s):  
S. Polydorides ◽  
G. Archontis
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Protein Design ◽  
Md Simulations ◽  
Binding Motif ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Computational Optimization ◽  
Binding Domains ◽  
Viral Sequences

ABSTRACTThe coronavirus SARS-CoV-2, that is responsible for the COVID-19 pandemic, and the closely related SARS-CoV coronavirus enter cells by binding at the human angiotensin converting enzyme 2 (hACE2). The stronger hACE2 affinity of SARS-CoV-2 has been connected with its higher infectivity. In this work, we study hACE2 complexes with the receptor binding domains (RBDs) of the human SARS-CoV-2 and human SARS-CoV viruses, using all-atom molecular dynamics (MD) simulations and Computational Protein Design (CPD) with a physics-based energy function. The MD simulations identify charge-modifying substitutions between the CoV-2 and CoV RBDs, which either increase or decrease the hACE2 affinity of the SARS-CoV-2 RBD. The combined effect of these mutations is small, and the relative affinity is mainly determined by substitutions at residues in contact with hACE2. Many of these findings are in line and interpret recent experiments. Our CPD calculations redesign positions 455, 493, 494 and 501 of the SARS-CoV-2 RBM, which contact hACE2 in the complex and are important for ACE2 recognition. Sampling is enhanced by an adaptive importance sampling Monte Carlo method. Sequences with increased affinity replace CoV-2 glutamine by a negative residue at position 493, and serine by nonpolar, aromatic or a threonine at position 494. Substitutions at positions positions 455 and 501 have a smaller effect on affinity. Substitutions suggested by our design are seen in viral sequences encountered in other species, including bat and pangolin. Our results might be used to identify potential virus strains with higher human infectivity and assist in the design of peptide-based or peptidomimetic compounds with the potential to inhibit SARS-CoV-2 binding at hACE2.SIGNIFICANCEThe coronavirus SARS-CoV-2 is responsible for the current COVID-19 pandemic. SARS-CoV-2 and the earlier, closely related SARS-CoV virus bind at the human angiotensin converting enzyme 2 (hACE2) receptor at the cell surface. The higher human infectivity of SARS-CoV-2 may be linked to its stronger affinity for hACE2. Here, we study by computational methods complexes of hACE2 with the receptor binding domains (RBDs) of viruses SARS-CoV-2 and SARS-CoV. We identify residues affecting the affinities of the two domains for hACE2. We also propose mutations at key SARS-CoV-2 positions, which might enhance hACE2 affinity. Such mutations may appear in viral strains with increased human infectivity and might assist the design of peptide-based compounds that inhibit infection of human cells by SARS-CoV-2.

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