Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity and Pathogenesis?

2020 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Alessandra Magistrato
Keyword(s):  
Health Economic ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
High Affinity ◽  
Global Pandemic ◽  
Medical Countermeasures ◽  
High Infectivity ◽  
Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

scholarly journals Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? An Answer from All-Atoms Simulations

2020 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Alessandra Magistrato
Keyword(s):  
Health Economic ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
High Affinity ◽  
Global Pandemic ◽  
Medical Countermeasures ◽  
High Infectivity ◽  
Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

scholarly journals Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? An Answer from All-Atoms Simulations

2020 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Alessandra Magistrato
Keyword(s):  
Health Economic ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
High Affinity ◽  
Global Pandemic ◽  
Medical Countermeasures ◽  
High Infectivity ◽  
Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

scholarly journals Is the Rigidity of SARS-CoV-2 Spike Receptor-Binding Motif the Hallmark for Its Enhanced Infectivity? An Answer from All-Atoms Simulations

2020 ◽  
Author(s):  
Angelo Spinello ◽  
Andrea Saltalamacchia ◽  
Alessandra Magistrato
Keyword(s):  
Health Economic ◽  
Global Health ◽  
Receptor Binding ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
High Affinity ◽  
Global Pandemic ◽  
Medical Countermeasures ◽  
High Infectivity ◽  
Human Receptor

<p>The latest outbreak of a new pathogenic coronavirus (SARS-CoV-2) is provoking a global health, economic and societal crisis. All-atom simulations enabled us to uncover the key molecular traits underlying the high affinity of SARS-CoV-2 spike glycoprotein towards its human receptor, providing a rationale to its high infectivity. Harnessing this knowledge can boost developing effective medical countermeasures to fight the current global pandemic.</p>

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 SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2

2021 ◽  
Author(s):  
Claire M. Weekley ◽  
Damian F. J. Purcell ◽  
Michael W. Parker
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Direct Interaction ◽  
Binding Domain ◽  
Spike Protein ◽  
Genomic Sequencing ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Structural Characterisation ◽  
Human Receptor

AbstractSince SARS-CoV-2 emerged in 2019, genomic sequencing has identified mutations in the viral RNA including in the receptor-binding domain of the Spike protein. Structural characterisation of the Spike carrying point mutations aids in our understanding of how these mutations impact binding of the protein to its human receptor, ACE2, and to therapeutic antibodies. The Spike G485R mutation has been observed in multiple isolates of the virus and mutation of the adjacent residue E484 to lysine is known to contribute to antigenic escape. Here, we have crystallised the SARS-CoV-2 Spike receptor-binding domain with a G485R mutation in complex with human ACE2. The crystal structure shows that while the G485 residue does not have a direct interaction with ACE2, its mutation to arginine affects the structure of the loop made by residues 480-488 in the receptor-binding motif, disrupting the interactions of neighbouring residues with ACE2 and with potential implications for antigenic escape from vaccines, antibodies and other biologics directed against SARS-CoV-2 Spike.

scholarly journals Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257905
Author(s):  
Van A. Ngo ◽  
Ramesh K. Jha
Keyword(s):  
Receptor Binding ◽  
Dissociation Rate ◽  
Receptor Protein ◽  
Terminal Part ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Interface ◽  
Global Pandemic ◽  
Key Residues ◽  
Insight Into ◽  
Human Receptor

SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for an invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS-CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make the RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in a reduced dissociation rate of SARS-CoV-2 from human receptor protein compared to SARS-CoV. The phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study adds more insight into the critical dynamics of the key residues at the virus spike and human receptor binding interface and potentially aids the development of diagnostics and therapeutics to combat the pandemic efficiently.

scholarly journals A high-affinity RBD-targeting nanobody improves fusion partner’s potency against SARS-CoV-2

2021 ◽  
Vol 17 (3) ◽  
pp. e1009328
Author(s):  
Hebang Yao ◽  
Hongmin Cai ◽  
Tingting Li ◽  
Bingjie Zhou ◽  
Wenming Qin ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Motif ◽  
Fusion Partner ◽  
Receptor Binding Domain ◽  
Single Chain ◽  
Neutralization Activity ◽  
Effective Strategies ◽  
High Affinity ◽  
Considerable Research

A key step to the SARS-CoV-2 infection is the attachment of its Spike receptor-binding domain (S RBD) to the host receptor ACE2. Considerable research has been devoted to the development of neutralizing antibodies, including llama-derived single-chain nanobodies, to target the receptor-binding motif (RBM) and to block ACE2-RBD binding. Simple and effective strategies to increase potency are desirable for such studies when antibodies are only modestly effective. Here, we identify and characterize a high-affinity synthetic nanobody (sybody, SR31) as a fusion partner to improve the potency of RBM-antibodies. Crystallographic studies reveal that SR31 binds to RBD at a conserved and ‘greasy’ site distal to RBM. Although SR31 distorts RBD at the interface, it does not perturb the RBM conformation, hence displaying no neutralizing activities itself. However, fusing SR31 to two modestly neutralizing sybodies dramatically increases their affinity for RBD and neutralization activity against SARS-CoV-2 pseudovirus. Our work presents a tool protein and an efficient strategy to improve nanobody potency.

scholarly journals Thiol-based mucolytics exhibit antiviral activity against SARS-CoV-2 through allosteric disulfide disruption in the spike glycoprotein

2021 ◽  
Author(s):  
Yunlong Shi ◽  
Ari Zeida ◽  
Caitlin E Edwards ◽  
Michael L Mallory ◽  
Santiago Sastre ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Receptor Binding ◽  
Binding Pocket ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
Hydrophobic Binding ◽  
Human Coronaviruses ◽  
Small Molecule Therapeutics ◽  
Computational Analyses ◽  
Mucolytic Agents

Small molecule therapeutics targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have lagged far behind the development of vaccines in the fight to control the COVID-19 pandemic. Here, we show that thiol-based mucolytic agents, P2119 and P2165, potently inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity of repurposed mucolytic agents to the reduction of key disulfides, specifically, by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif (RBM) in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol warhead pointed directly towards Cys432. These collective findings establish the vulnerability of human coronaviruses to repurposed thiol-based mucolytics and lay the groundwork for developing these compounds as a potential treatment, preventative and/or adjuvant against infection.

scholarly journals A high-affinity RBD-targeting nanobody improves fusion partner’s potency against SARS-CoV-2

2020 ◽  
Author(s):  
Hebang Yao ◽  
Hongmin Cai ◽  
Tingting Li ◽  
Bingjie Zhou ◽  
Wenming Qin ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Binding Motif ◽  
Fusion Partner ◽  
Receptor Binding Domain ◽  
Single Chain ◽  
Neutralization Activity ◽  
Effective Strategies ◽  
High Affinity ◽  
Considerable Research

ABSTRACTA key step to the SARS-CoV-2 infection is the attachment of its Spike receptor-binding domain (S RBD) to the host receptor ACE2. Considerable research have been devoted to the development of neutralizing antibodies, including llama-derived single-chain nanobodies, to target the receptor-binding motif (RBM) and to block ACE2-RBD binding. Simple and effective strategies to increase potency are desirable for such studies when antibodies are only modestly effective. Here, we identify and characterize a high-affinity synthetic nanobody (sybody, SR31) as a fusion partner to improve the potency of RBM-antibodies. Crystallographic studies reveal that SR31 binds to RBD at a conserved and ‘greasy’ site distal to RBM. Although SR31 distorts RBD at the interface, it does not perturb the RBM conformation, hence displaying no neutralizing activities itself. However, fusing SR31 to two modestly neutralizing sybodies dramatically increases their affinity for RBD and neutralization activity against SARS-CoV-2 pseudovirus. Our work presents a tool protein and an efficient strategy to improve nanobody potency.

scholarly journals Structural Analysis Of The Receptor Binding Motif Of Spike Glycoprotein Explains The High Stability Of SARS-CoV-2 RBD/hACE2-complex

2020 ◽  
Author(s):  
Akshay Nileshkumar Pandya
Keyword(s):  
Structural Analysis ◽  
Host Cell ◽  
Receptor Binding ◽  
Structural Changes ◽  
Host Cells ◽  
Binding Motif ◽  
Spike Glycoprotein ◽  
Furin Cleavage ◽  
Furin Cleavage Site ◽  
The Stability

SARS-CoV and SARS-CoV-2 both are the Coronaviruses causing Severe Acute Respiratory Syndrome(SARS). Genomes of both SARS-viruses are identical and they both use Spike glycoprotein to enter the host cell. hACE2(human Angiotensin-Converting Enzyme) is the receptor used by both viruses to enter the host cell. Despite the similar structures, the SARS-CoV-2 is more infective compared to the SARS-CoV. As the SARS-CoV-2 RBD/hACE2 complex is more stable compared to the SARS-CoV RBD/hACE2 complex, the SARS-CoV-2 is more effective in terms of entering the host cells. Structural analysis revealed that the addition of a Furin cleavage site and the structural changes in Receptor Binding Domain(RBD) of the Spike protein are mainly responsible for this increase in the stability. Differences between the structure of the Spike glycoproteins of SARS-CoV and SARS-CoV-2 are discussed in-depth and an attempt to correlate them with increased infectivity of the SARS-CoV-2(compared to the SARS-CoV) is made.

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