Modeling SARS-CoV-2 spike/ACE2 protein-protein interactions for predicting the binding affinity of new spike variants for ACE2, and novel ACE2 structurally related human protein targets, for COVID-19 handling in the 3PM context.
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ABSTRACT:
SUBMITTER: Tragni V
PROVIDER: S-EPMC8732965 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Coronaviruses (CoVs) pose a major risk to global public health due to their ability to infect diverse animal species and potential for emergence in humans. The CoV spike protein mediates viral entry into the cell and plays a crucial role in determining the binding affinity to host cell receptors. With particular emphasis on α- and β-coronaviruses that infect humans and domestic animals, current research on CoV receptor use suggests that the exploitation of the angiotensin-converting enzyme 2 (ACE2) receptor poses a significant threat for viral emergence with pandemic potential. This review summarizes the approaches used to study binding interactions between CoV spike proteins and the human ACE2 (hACE2) receptor. Solid-phase enzyme immunoassays and cell binding assays allow qualitative assessment of binding but lack quantitative evaluation of affinity. Surface plasmon resonance, Bio-layer interferometry, and Microscale Thermophoresis on the other hand, provide accurate affinity measurement through equilibrium dissociation constants (KD). In silico modeling predicts affinity through binding structure modeling, protein-protein docking simulations, and binding energy calculations but reveals inconsistent results due to the lack of a standardized approach. Machine learning and deep learning models utilize simulated and experimental protein-protein interaction data to elucidate the critical residues associated with CoV binding affinity to hACE2. Further optimization and standardization of existing approaches for studying binding affinity could aid pandemic preparedness. Specifically, prioritizing surveillance of CoVs that can bind to human receptors stands to mitigate the risk of zoonotic spillover.
| S-EPMC10831124 | biostudies-literature
Project description:A novel coronavirus (SARS-CoV-2) has emerged to a global pandemic and caused significant damages to public health. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides Ang II to control vasodilatation and permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we wonder how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ~3-10 fold when fluorogenic caspase-1 substrate and Bradykinin-analog peptides were used to characterize ACE2 activity. In addition, the enhancement was mediated by ACE2 binding of RBD domain of SARS-CoV-2 spike. These results highlighted the altered activity of ACE2 during SARS-CoV-2 infection and would shed new lights on the pathogenesis of COVID-19 and its complications for better treatments.
| S-EPMC7337377 | biostudies-literature
Project description:The novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) has emerged to a pandemic and caused global public health crisis. Human angiotensin-converting enzyme 2(ACE2) was identified as the entry receptor for SARS-CoV-2. As a carboxypeptidase, ACE2 cleaves many biological substrates besides angiotensin II to control vasodilatation and vascular permeability. Given the nanomolar high affinity between ACE2 and SARS-CoV-2 spike protein, we investigated how this interaction would affect the enzymatic activity of ACE2. Surprisingly, SARS-CoV-2 trimeric spike protein increased ACE2 proteolytic activity ∼3-10 fold against model peptide substrates, such as caspase-1 substrate and Bradykinin-analog. The enhancement in ACE2 enzymatic function was mediated by the binding of SARS-CoV-2 spike RBD domain. These results highlighted the potential for SARS-CoV-2 infection to enhance ACE2 activity, which may be relevant to the cardiovascular symptoms associated with COVID-19.
| S-EPMC7833600 | biostudies-literature
Project description:The development of countermeasures that aid in the prevention and propagation of SARS-CoV-2 infections is critical to manage the continuing crisis brought about by COVID-19. Here we present a proof-of-concept study on the use of cell-mimetic microparticles (Cytomimetics) for the interference and sequestration of SARS-CoV-2 virions away from the cellular surfaces required for replication, disease manifestation, and outbreak propagation. Recombinant human ACE2 (rhACE2) functionalized onto the surface of cytomimetic particles binds the receptor binding domain (RBD) of recombinant SARS-CoV-2 spike protein with high affinity and demonstrated a stoichiometric advantage over the use of soluble rhACE2. Inhalation of rhACE2-Cytomimetic particles by mice prior to their exposure to aerosolized spike protein demonstrated the applicability of these cytomimetic particles in preventing viral protein binding to respiratory epithelial cells. Our study demonstrates the potential of an easily deliverable and highly modular technology for the control of viral infections and to complement other prophylactic countermeasures.
| S-EPMC8482554 | biostudies-literature
Project description:There is increasing evidence that ACE2 gene polymorphism can modulate the interaction between ACE2 and the SARS-CoV-2 spike protein affecting the viral entry into the host cell, and/or contribute to lung and systemic damage in COVID-19. Here we used in silico molecular docking to predict the effects of ACE2 missense variants on the interaction with the spike protein of SARS-CoV-2. HDOCK and FireDock simulations identified 6 ACE2 missense variants (I21T, A25T, K26R, E37K, T55A, E75G) with higher affinity for SARS-CoV-2 Spike protein receptor binding domain (RBD) with respect to wild type ACE2, and 11 variants (I21V, E23K, K26E, T27A, E35K, S43R, Y50F, N51D, N58H, K68E, M82I) with lower affinity. This result supports the hypothesis that ACE2 genetic background may represent the first "genetic gateway" during the disease progression.
| S-EPMC7834737 | biostudies-literature
Project description:Even with the availability of vaccines, therapeutic options for COVID-19 still remain highly desirable, especially in hospitalized patients with moderate or severe disease. Soluble ACE2 (sACE2) is a promising therapeutic candidate that neutralizes SARS CoV-2 infection by acting as a decoy. Using computational mutagenesis, we designed a number of sACE2 derivatives carrying three to four mutations. The top-predicted sACE2 decoy based on the in silico mutagenesis scan was subjected to molecular dynamics and free-energy calculations for further validation. After illuminating the mechanism of increased binding for our designed sACE2 derivative, the design was verified experimentally by flow cytometry and BLI-binding experiments. The computationally designed sACE2 decoy (ACE2-FFWF) bound the receptor-binding domain of SARS-CoV-2 tightly with low nanomolar affinity and ninefold affinity enhancement over the wild type. Furthermore, cell surface expression was slightly greater than wild-type ACE2, suggesting that the design is well-folded and stable. Having an arsenal of high-affinity sACE2 derivatives will help to buffer against the emergence of SARS CoV-2 variants. Here, we show that computational methods have become sufficiently accurate for the design of therapeutics for current and future viral pandemics.
| S-EPMC8409145 | biostudies-literature
Project description: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 the recognition of the binding ACE2 proteins is the first step for the coronaviruses to invade host cells, we proposed 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 on the modeled Spike-RBD/ACE2 complex structures correlate closely with the effectiveness of animal infections as determined by multiple experimental datasets. Built on the optimized binding affinity cutoff, we suggested 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 suggested a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation; but more importantly, it proposed a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.
| S-EPMC7491519 | biostudies-literature
Project description:COVID-19 is a new communicable disease with a widespread outbreak that affects all populations worldwide triggering a rush of scientific interest in coronavirus research globally. In silico molecular docking experiment was utilized to determine interactions of available compounds with SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2) complex. Chimera and AutoDock Vina were used for protein-ligand interaction structural analysis. Ligands were chosen based on the known characteristics and indications of the drugs as ACE inhibitors (captopril, enalapril, quinapril, moexipril, benazepril, ramipril, perindopril, zofenopril, fosinopril), as ACE2 blockers (losartan, olmesartan), as blood thinning agent (clopidogrel), as cholesterol-lowering prescriptions (simvastatin, atorvastatin), repurposed medications (dexamethasone, hydroxychloroquine, chloroquine), and as investigational drug (remdesivir). Experimental ACE/ACE2 inhibitors are also included: Sigma ACEI, N-(2-aminoethyl)-1-aziridine-ethanamine (NAAE), nicotianamine (NAM), and MLN-4760 (ACE2 inhibitor). The best docked conformations were all located in the ACE2 protein, 50% docked at the interface with lower scores and only clopidogrel and hydroxychloroquine docked at the spike protein. Captopril, moexipril, benazepril, fosinopril, losartan, remdesivir, Sigma ACEI, NAA, and NAM interacted and docked at the interface of ACE2 and SARS-CoV-2 spike protein complex. This may have significant implication in enhancing our understanding of the mechanism to hinder viral entry into the host organism during infection.Supplementary informationThe online version contains supplementary material available at 10.1007/s40203-021-00114-w.
| S-EPMC8495439 | biostudies-literature
Project description:The recognition of ACE2 by the receptor-binding domain (RBD) of spike protein mediates host cell entry. The objective of the work is to identify SARS-CoV2 spike variants that emerged during the pandemic and evaluate their binding affinity with ACE2. Evolutionary analysis of 2178 SARS-CoV2 genomes identifies RBD variants that are under selection bias. The binding efficacy of these RBD variants to the ACE2 has been analyzed by using protein-protein docking and binding free energy calculations. Pan-proteomic analysis reveals 113 mutations among them 33 are parsimonious. Evolutionary analysis reveals five RBD variants A348T, V367F, G476S, V483A, and S494P are under strong positive selection bias. Variations at these sites alter the ACE2 binding affinity. A348T, G476S, and V483A variants display reduced affinity to ACE2 in comparison to the Wuhan SARS-CoV2 spike protein. While the V367F and S494P population variants display a higher binding affinity towards human ACE2. Reorientation of several crucial residues at the RBD-ACE2 interface facilitates additional hydrogen bond formation for the V367F variant which enhances the binding energy during ACE2 recognition. On the other hand, the enhanced binding affinity of S494P is attributed to strong interfacial complementarity between the RBD and ACE2.
| S-EPMC7699163 | biostudies-literature
Project description:The recognition of ACE2 by the receptor-binding domain (RBD) of spike protein mediates host cell entry. The objective of the work is to identify SARS-CoV2 spike variants that emerged during the pandemic and evaluate their binding affinity with ACE2. Evolutionary analysis of 2178 SARS-CoV2 genomes identifies RBD variants that are under selection bias. The binding efficacy of these RBD variants to the ACE2 has been analyzed by using protein-protein docking and binding free energy calculations. Pan-proteomic analysis reveals 113 mutations among them 33 are parsimonious. Evolutionary analysis reveals five RBD variants A348T, V367F, G476S, V483A, and S494P are under strong positive selection bias. Variations at these sites alter the ACE2 binding affinity. A348T, G476S, and V483A variants display reduced affinity to ACE2 in comparison to the Wuhan SARS-CoV2 spike protein. While the V367F and S494P population variants display a higher binding affinity towards human ACE2. Reorientation of several crucial residues at the RBD-ACE2 interface facilitates additional hydrogen bond formation for the V367F variant which enhances the binding energy during ACE2 recognition. On the other hand, the enhanced binding affinity of S494P is attributed to strong interfacial complementarity between the RBD and ACE2.
| S-EPMC7883683 | biostudies-literature