ACE2-Variants Indicate Potential SARS-CoV-2-Susceptibility in Animals: An Extensive Molecular Dynamics Study (original) (raw)
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2020
The novel coronavirus SARS-CoV-2 is the cause of Coronavirus Disease-2019 (COVID-19). The main receptor of SARS-CoV-2, angiotensin I converting enzyme 2 (ACE2), is now undergoing extensive scrutiny to understand the routes of transmission and sensitivity in different species. Here, we utilized a unique dataset of 410 vertebrates, including 252 mammals, to study cross-species conservation of ACE2 and its likelihood to function as a SARS-CoV-2 receptor. We designed a five-category ranking score based on the conservation properties of 25 amino acids important for the binding between receptor and virus, classifying all species fromvery hightovery low. Only mammals fell into themediumtovery highcategories, and only catarrhine primates in thevery highcategory, suggesting that they are at high risk for SARS-CoV-2 infection. We employed a protein structural analysis to qualitatively assess whether amino acid changes at variable residues would be likely to disrupt ACE2/SARS-CoV-2 binding, an...
3 Biotech
SARS-CoV-2, which causes severe pneumonia epidemics, probably originated from Chinese horseshoe bats, but the intermediate and host range is still unknown. ACE2 is the entry receptor for SARS-CoV-2. The binding capacity of SARS-CoV-2 spike protein to ACE2 is the critical determinant of viral host range and cross-species infection. Here, we used an in silico approach to predict the potential animals range with high susceptibility to SARS-CoV-2 by modelling and studying the Spike-ACE2 interaction of 22 domestic and wild animals. Our results showed that all studied animals are potentially susceptible to SARS-CoV-2 infection with a slight difference in the binding affinity and stability of their ACE2-RBD complexes. Furthermore, we identified a specific substitution of tyrosine to histidine at position 41 in ACE2 that likely reduces the affinity to SARS-CoV-2 in horses and greater horseshoe bats. These results may help to provide important insights into SARS-CoV-2 host range which will make it possible to control the spread of the virus and identify animal models that could be used for screening antiviral drugs or vaccine candidates against SARS-CoV-2.
International Journal of Molecular Sciences
After a sudden and first spread of the pandemic caused by the novel SARS-CoV-2 (Severe Acute Respiratory Syndrome—Coronavirus 2) wild-type strain, mutants have emerged which have been associated with increased infectivity, inducing surges in the contagions. The first of the so-called variants of concerns, was firstly isolated in the United Kingdom and later renamed Alpha variant. Afterwards, in the middle of 2021, a new variant appeared called Delta. The latter is characterized by the presence of point mutations in the Spike protein of SARS-CoV-2, especially in the Receptor Binding Domain (RBD). When in its active conformation, the RBD can interact with the human receptor Angiotensin-Converting Enzyme 2 (ACE2) to allow the entry of the virions into cells. In this contribution, by using extended all-atom molecular dynamic simulations, complemented with machine learning post-processing, we analyze the changes in the molecular interaction network induced by these different strains in c...
Predicting mammalian species at risk of being infected by SARS-CoV-2 from an ACE2 perspective
Scientific Reports
SARS-CoV-2 can transmit efficiently in humans, but it is less clear which other mammals are at risk of being infected. SARS-CoV-2 encodes a Spike (S) protein that binds to human ACE2 receptor to mediate cell entry. A species with a human-like ACE2 receptor could therefore be at risk of being infected by SARS-CoV-2. We compared between 132 mammalian ACE2 genes and between 17 coronavirus S proteins. We showed that while global similarities reflected by whole ACE2 gene alignments are poor predictors of high-risk mammals, local similarities at key S protein-binding sites highlight several high-risk mammals that share good ACE2 homology with human. Bats are likely reservoirs of SARS-CoV-2, but there are other high-risk mammals that share better ACE2 homologies with human. Both SARS-CoV-2 and SARS-CoV are closely related to bat coronavirus. Yet, among host-specific coronaviruses infecting high-risk mammals, key ACE2-binding sites on S proteins share highest similarities between SARS-CoV-2...
The pandemic of Coronavirus Disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major global health threat. Epidemiological studies suggest that bats are the natural zoonotic reservoir for SARS-CoV-2. However, the host range of SARS-CoV-2 and intermediate hosts that facilitate its transmission to humans remain unknown. The interaction of coronavirus with its host receptor is a key genetic determinant of host range and cross-species transmission. SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as the receptor to enter host cells in a species-dependent manner. It has been shown that human, palm civet, pig and bat ACE2 can support virus entry, while the murine ortholog cannot. In this study, we characterized the ability of ACE2 from diverse species to support viral entry. We found that ACE2 is expressed in a wide range of species, with especially high conservation in mammals. By analyzing amino acid residues of ACE2 critical for ...
Diversity of ACE2 and its interaction with SARS-CoV-2 receptor binding domain
Biochemical Journal
COVID-19, the clinical syndrome caused by the SARS-CoV-2 virus, has rapidly spread globally causing hundreds of millions of infections and over two million deaths. The potential animal reservoirs for SARS-CoV-2 are currently unknown, however sequence analysis has provided plausible potential candidate species. SARS-CoV-2 binds to the angiotensin I converting enzyme 2 (ACE2) to enable its entry into host cells and establish infection. We analyzed the binding surface of ACE2 from several important animal species to begin to understand the parameters for the ACE2 recognition by the SARS-CoV-2 spike protein receptor binding domain (RBD). We employed Shannon entropy analysis to determine the variability of ACE2 across its sequence and particularly in its RBD interacting region, and assessed differences between various species’ ACE2 and human ACE2. Recombinant ACE2 from human, hamster, horseshoe bat, cat, ferret, and cow were evaluated for RBD binding. A gradient of binding affiniti...
The flexibility of ACE2 in the context of SARS-CoV-2 infection
2020
The COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region conn...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the Spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures to contain the spread of the disease in many countries has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread and whether they can cause a more severe disease remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (KD) values using surface plasmon resonance (SPR) assays of three fastspreading SARS-CoV-2 variants, Alpha, Beta and Gamma ones, as well as genetic factors in the host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by R...
Journal of Proteome Research, 2020
Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that binding to ACE2 proteins is the first step for the coronaviruses to invade host cells, we propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets. Built on the optimized binding affinity cutoff, we suggest a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggests a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation, but also, more importantly, it proposes a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.
2021
The total impact of the worldwide COVID-19 pandemic is still emerging, changing all relationships as a result, including those with pet animals. In the infection process, the use of Angiotensin-converting enzyme 2 (ACE2) as a cellular receptor to the spike protein of the new coronavirus is a fundamental step. In this sense, understanding which residue plays what role in the interaction between SARS-CoV-2 spike glycoprotein and ACE2 from cats, dogs, and ferrets is an important guide for helping to choose which animal model can be used to study the pathology of COVID-19 and if there are differences between these interactions and those occurring in the human system. Hence, trying to help to answer these questions, we performed classical molecular dynamics simulations to evaluate, from an atomistic point of view, the interactions in these systems. Our results show that there are significant differences in the interacting residues between the systems from different animal species, and th...