scholarly journals Thermodynamics of the Interaction Between SARS-CoV-2 Spike Protein and Human ACE2 Receptor. Effects of Possible Ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Design ◽  
State Of The Art ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

scholarly journals Thermodynamics of the Interaction Between SARS-CoV-2 Spike Protein and Human ACE2 Receptor. Effects of Possible Ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Molecular Design ◽  
State Of The Art ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

scholarly journals Thermodynamics of the interaction between the spike protein of severe acute respiratory syndrome- coronavirus-2 and the receptor of human angiotensin converting enzyme 2. Effects of possible ligands

2020 ◽  
Author(s):  
Cristina Garcia-Iriepa ◽  
Cecilia Hognon ◽  
Antonio Francés-Monerris ◽  
Isabel Iriepa ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Molecular Mechanisms ◽  
Molecular Design ◽  
Binding Free Energy ◽  
Transmembrane Protein ◽  
Spike Protein ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Rational Molecular Design ◽  
Rational Evaluation

<div><p>Since the end of 2019, the coronavirus SARS-CoV-2 has caused more than 180,000 deaths all over the world, still lacking a medical treatment despite the concerns of the whole scientific community. Human Angiotensin-Converting Enzyme 2 (ACE2) was recently recognized as the transmembrane protein serving as SARS-CoV-2 entry point into cells, thus constituting the first biomolecular event leading to COVID-19 disease. Here, by means of a state-of-the-art computational approach, we propose a rational evaluation of the molecular mechanisms behind the formation of the complex and of the effects of possible ligands. Moreover, binding free energy between ACE2 and the active Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is evaluated quantitatively, assessing the molecular mechanisms at the basis of the recognition and the ligand-induced decreased affinity. These results boost the knowledge on the molecular grounds of the SARS-CoV-2 infection and allow to suggest rationales useful for the subsequent rational molecular design to treat severe COVID-19 cases.</p></div>

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 The basis of a more contagious 501Y.V1 variant of SARS-COV-2

2021 ◽  
Author(s):  
Haolin Liu ◽  
Qianqian Zhang ◽  
Pengcheng Wei ◽  
Zhongzhou Chen ◽  
Katja Aviszus ◽  
...  
Keyword(s):  
World Wide ◽  
Spike Protein ◽  
Single Mutation ◽  
Receptor Binding Domain ◽  
Angiotensin Converting Enzyme 2 ◽  
The United Kingdom ◽  
Modeling Analysis ◽  
Additional Hydrogen Bond ◽  
Ring Interaction ◽  
Additional Hydrogen

AbstractSevere acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing a world-wide pandemic. A variant of SARS-COV-2 (20I/501Y.V1) recently discovered in the United Kingdom has a single mutation from N501 to Y501 within the receptor binding domain (Y501-RBD), of the Spike protein of the virus. This variant is much more contagious than the original version (N501-RBD). We found that this mutated version of RBD binds to human Angiotensin Converting Enzyme 2 (ACE2) a ~10 times more tightly than the native version (N501-RBD). Modeling analysis showed that the N501Y mutation would allow a potential aromatic ring-ring interaction and an additional hydrogen bond between the RBD and ACE2. However, sera from individuals immunized with the Pfizer-BioNTech vaccine still efficiently block the binding of Y501-RBD to ACE2 though with a slight compromised manner by comparison with their ability to inhibit binding to ACE2 of N501-RBD. This may raise the concern whether therapeutic anti-RBD antibodies used to treat COVID-19 patients are still efficacious. Nevertheless, a therapeutic antibody, Bamlanivimab, still binds to the Y501-RBD as efficiently as its binds to N501-RBD.

scholarly journals Omicron SARS-CoV-2 Variant Spike Protein Shows an Increased Affinity to the Human ACE2 Receptor: An In Silico Analysis

Pathogens ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 45
Author(s):  
Joseph Thomas Ortega ◽  
Beata Jastrzebska ◽  
Hector Rafael Rangel
Keyword(s):  
Free Energy ◽  
Electrostatic Interactions ◽  
Structural Model ◽  
Binding Free Energy ◽  
In Silico Analysis ◽  
Spike Protein ◽  
Medical Community ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Silico Analysis

The rise of SARS-CoV-2 variants, with changes that could be related to an increased virus pathogenicity, have received the interest of the scientific and medical community. In this study, we evaluated the changes that occurred in the viral spike of the SARS-CoV-2 Omicron variant and whether these changes modulate the interactions with the angiotensin-converting enzyme 2 (ACE2) host receptor. The mutations associated with the Omicron variant were retrieved from the GISAID and covariants.org databases, and a structural model was built using the SWISS-Model server. The interaction between the spike and the human ACE2 was evaluated using two different docking software, Zdock and Haddock. We found that the binding free energy was lower for the Omicron variant as compared to the WT spike. In addition, the Omicron spike protein showed an increased number of electrostatic interactions with ACE2 than the WT spike, especially the interactions related to charged residues. This study contributes to a better understanding of the changes in the interaction between the Omicron spike and the human host ACE2 receptor.

scholarly journals Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

2021 ◽  
Author(s):  
Vincent Dussupt ◽  
Rajeshwer S. Sankhala ◽  
Letzibeth Mendez-Rivera ◽  
Samantha M. Townsley ◽  
Fabian Schmidt ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Low Dose ◽  
Viral Escape ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Inactivation ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Monoclonal Antibodies ◽  
Potent Protection

AbstractPrevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

scholarly journals Dynamics of the ACE2 - SARS-CoV/SARS-CoV-2 spike protein interface reveal unique mechanisms

2020 ◽  
Author(s):  
Amanat Ali ◽  
Ranjit Vijayan
Keyword(s):  
Salt Bridge ◽  
Spike Protein ◽  
Health Concern ◽  
Treatment Modalities ◽  
Receptor Binding Domain ◽  
Public Health Concern ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations ◽  
And Function ◽  
Host Target

AbstractThe coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple all atom molecular dynamics simulations of at least 500 ns each were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV and SARS-CoV-2 utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 spike protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493, and Gln498 of SARS-CoV-2 and Asp38, Glu35, and Lys353 of ACE2 were observed, which were absent in the SARS-CoV-ACE2 interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.

scholarly journals Structural Dissection of Viral Spike-Protein Binding of SARS-CoV-2 and SARS-CoV-1 to the Human Angiotensin-Converting Enzyme 2 (ACE2) as Cellular Receptor

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1038
Author(s):  
Deborah Giordano ◽  
Luigi De Masi ◽  
Maria Antonia Argenio ◽  
Angelo Facchiano
Keyword(s):  
Angiotensin Converting Enzyme ◽  
In Silico Analysis ◽  
Host Cells ◽  
Spike Protein ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
The World ◽  
Silico Analysis

An outbreak by a new severe acute respiratory syndrome betacoronavirus (SARS-CoV-2) has spread CoronaVirus Disease 2019 (COVID-19) all over the world. Immediately, following studies have confirmed the human Angiotensin-Converting Enzyme 2 (ACE2) as a cellular receptor of viral Spike-Protein (Sp) that mediates the CoV-2 invasion into the pulmonary host cells. Here, we compared the molecular interactions of the viral Sp from previous SARS-CoV-1 of 2002 and SARS-CoV-2 with the host ACE2 protein by in silico analysis of the available experimental structures of Sp-ACE2 complexes. The K417 amino acid residue, located in the region of Sp Receptor-Binding Domain (RBD) of the new coronavirus SARS-CoV-2, showed to have a key role for the binding to the ACE2 N-terminal region. The R426 residue of SARS-CoV-1 Sp-RBD also plays a key role, although by interacting with the central region of the ACE2 sequence. Therefore, our study evidenced peculiarities in the interactions of the two Sp-ACE2 complexes. Our outcomes were consistent with previously reported mutagenesis studies on SARS-CoV-1 and support the idea that a new and different RBD was acquired by SARS-CoV-2. These results have interesting implications and suggest further investigations.

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