Coronavirus Spike Glycoprotein Research Articles

Synthesis of Cobalt(III) Complexes Derived from Pyridoxal: Structural Cleavage Evaluations and In Silico Calculations for Biological Targets

This study sought to investigate the synthesis of eight complexes constituted by a cobalt(III) (CoIII) metallic center coordinated to two units of iminic ligands LnC (n = 1–4, L1C–L4C), which are derivatives of pyridoxal hydrochloride and anilines with thioether function containing one to four carbons. Depending on the source of the cobalt ion and the addition (or not) of a non-coordinating counterion, complexes with distinct structures may form, being categorized into two series: [CoIII(LnC)(L0C)] (n = 1–4, C1’–C4’) with a LnC ligand and a ligand that has a thiolate function which cleaves the C-S(thioether) bond (L0C) and [CoIII(LnC)2]PF6 (n = 1–4, C1–C4) with two similar units of the same LnC ligand. The occurrence (or not) of cleavage in the eight complexes was observed by elucidating the solid-state structures by single crystal X-ray diffraction. This exciting method allows the synthesis of CoIII complexes without cleaving the C-S bonds from the ligands, thereby not requiring an inert atmosphere in the reaction systems. The synthesized complexes were evaluated by in silico calculations on viable biological targets such as deoxyribonucleic acid, superoxide dismutase enzyme, human serum albumin, and the structural spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the receptor binding domain (RBD) in both up and down conformations without and in complex with the cellular receptor angiotensin-converting enzyme 2 (ACE2). Overall, in silico results suggested that all the inorganic complexes under study are potential anticancer/antiviral agents; however, C4 and C4’ are the best candidates for future in vitro assays.

CD8+ T cell memory induced by successive SARS-CoV-2 mRNA vaccinations is characterized by shifts in clonal dominance

mRNA vaccines against the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) elicit strong Tcell responses. However, a clonal-resolution analysis of Tcell responses to mRNA vaccination has not been performed. Here, we temporally track the CD8+ Tcell repertoire in individuals who received three shots of the BNT162b2 mRNA vaccine through longitudinal Tcell receptor sequencing with peptide-human leukocyte antigen (HLA) tetramer analysis. We demonstrate a shift in Tcell responses between the clonotypes with different kinetics: from early responders that expand rapidly after the first shot to main responders that greatly expand after the second shot. Although the main responders re-expand after the third shot, their clonal diversity is skewed, and newly elicited third responders partially replace them. Furthermore, this shift in clonal dominance occurs not only between, but also within, clonotypes specific for spike epitopes. Our study will be a valuable resource for understanding vaccine-induced Tcell responses in general.

Abstract 1574 Structural insights into the dynamics of bat coronavirus spike glycoprotein

Abstract 1574 Structural insights into the dynamics of bat coronavirus spike glycoprotein

Natural products as a source of Coronavirus entry inhibitors.

The COVID-19 pandemic has had a significant and lasting impact on the world. Four years on, despite the existence of effective vaccines, the continuous emergence of new SARS-CoV-2 variants remains a challenge for long-term immunity. Additionally, there remain few purpose-built antivirals to protect individuals at risk of severe disease in the event of future coronavirus outbreaks. A promising mechanism of action for novel coronavirus antivirals is the inhibition of viral entry. To facilitate entry, the coronavirus spike glycoprotein interacts with angiotensin converting enzyme 2 (ACE2) on respiratory epithelial cells. Blocking this interaction and consequently viral replication may be an effective strategy for treating infection, however further research is needed to better characterize candidate molecules with antiviral activity before progressing to animal studies and clinical trials. In general, antiviral drugs are developed from purely synthetic compounds or synthetic derivatives of natural products such as plant secondary metabolites. While the former is often favored due to the higher specificity afforded by rational drug design, natural products offer several unique advantages that make them worthy of further study including diverse bioactivity and the ability to work synergistically with other drugs. Accordingly, there has recently been a renewed interest in natural product-derived antivirals in the wake of the COVID-19 pandemic. This review provides a summary of recent research into coronavirus entry inhibitors, with a focus on natural compounds derived from plants, honey, and marine sponges.

In-Silico Anti-SARS-CoV-2 Activity of Different Bioactives Green-Extracted from the Medicinal Plant Saussurea lappa Clarck

Since the COVID-19’s outbreak in 2019, efforts are continued to scan health and immune enhancing action of the historically known medicinal herbs. This paper describes a thorough in-silico method certain phytochemicals from Saussurea lappa Clarke, with a focus on the main protease (Mpro), papain like protease (PLpro) and the spike glycoprotein of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The aim of our study is to explore the green-extracted phyto-bioactive compounds’ activities as potential SARS-CoV-2 inhibitor. Unlike previous studies, this study tried to investigate most polar, semipolar and nonpolar compounds from S. lappa. The plant’s dried roots oil was extracted via supercritical CO2 extractor to collect the polar and semipolar compounds. The rest semipolar and polar compounds were hydroalcoholic extracted with (50%Ethanol) from the defatted residues by the aid of sonication, filtered and freeze-dried. The two fractions were chemically profiled by subjecting to HPLC and GC-MS analyses, and results revealed thirty-three different polyphenolic compounds and terpenoids. The distinguished bioactives were subjected to the in-silico study. Among these compounds, the most effective predicted inhibitors by molecular docking were ellagic acid and rutin as inhibitors for Mpro, spike protein and PLpro with vina scores equal -8.4, -8.9 and -11.6 respectively. As far as we know, this is the first study which reports the inhibitory activity against SARS-CoV-2 of both of the green extracted hydroalcoholic extract and oil of S. lappa in an attempt to examine as much as possible of the polar semipolar and nonpolar bioactives, which were very promising. However, this work interpret only one type of computational analysis of selected phyto-bioactive compounds and further surveys are required to confirm their suitability as anti-COVID-19 treatment.

Structural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans

Coronavirus spike glycoproteins presented on the virion surface mediate receptor binding, and membrane fusion during virus entry and constitute the primary target for vaccine and drug development. How the structure dynamics of the full-length spikes incorporated in viral lipid envelope correlates with the virus infectivity remains poorly understood. Here we present structures and distributions of native spike conformations on vitrified human coronavirus NL63 (HCoV-NL63) virions without chemical fixation by cryogenic electron tomography (cryoET) and subtomogram averaging, along with site-specific glycan composition and occupancy determined by mass spectrometry. The higher oligomannose glycan shield on HCoV-NL63 spikes than on SARS-CoV-2 spikes correlates with stronger immune evasion of HCoV-NL63. Incorporation of cryoET-derived native spike conformations into all-atom molecular dynamic simulations elucidate the conformational landscape of the glycosylated, full-length spike that reveals a role of hinge glycans in modulating spike bending. We show that glycosylation at N1242 at the upper portion of the stalk is responsible for the extensive orientational freedom of the spike crown. Subsequent infectivity assays implicated involvement of N1242-glyan in virus entry. Our results suggest a potential therapeutic target site for HCoV-NL63.

MULGA, a unified multi-view graph autoencoder-based approach for identifying drug-protein interaction and drug repositioning.

Identifying drug-protein interactions (DPIs) is a critical step in drug repositioning, which allows reuse of approved drugs that may be effective for treating a different disease and thereby alleviates the challenges of new drug development. Despite the fact that a great variety of computational approaches for DPI prediction have been proposed, key challenges, such as extendable and unbiased similarity calculation, heterogeneous information utilization and reliable negative sample selection, remain to be addressed. To address these issues, we propose a novel, unified multi-view graph autoencoder framework, termed MULGA, for both DPI and drug repositioning predictions. MULGA is featured by: (i) a multi-view learning technique to effectively learn authentic drug affinity and target affinity matrices; (ii) a graph autoencoder to infer missing DPI interactions; and (iii) a new "guilty-by-association"-based negative sampling approach for selecting highly reliable non-DPIs. Benchmark experiments demonstrate that MULGA outperforms state-of-the-art methods in DPI prediction and the ablation studies verify the effectiveness of each proposed component. Importantly, we highlight the top drugs shortlisted by MULGA that target the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2), offering additional insights into and potentially useful treatment option for COVID-19. Together with the availability of datasets and source codes, we envision that MULGA can be explored as a useful tool for DPI prediction and drug repositioning. MULGA is publicly available for academic purposes at https://github.com/jianiM/MULGA/. Supplementary data are available at Bioinformatics online.

Repurposing CRISPR/Cas to Discover SARS-CoV-2 Detecting and Neutralizing Aptamers.

RNA aptamers provide useful biological probes and therapeutic agents. New methodologies to screen RNA aptamers will be valuable by complementing the traditional Systematic Evolution of Ligands by Exponential Enrichment (SELEX). Meanwhile, repurposing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated systems (Cas) has expanded their utility far beyond their native nuclease function. Here, CRISmers, a CRISPR/Cas-based novel screening system for RNA aptamers based on binding to a chosen protein of interest in a cellular context, is presented. Using CRISmers, aptamers are identified specifically targeting the receptor binding domain (RBD) of the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two aptamer leads enable sensitive detection and potent neutralization of SARS-CoV-2 Delta and Omicron variants in vitro. Intranasal administration of one aptamer, further modified with 2'-fluoro pyrimidines (2'-F), 2'-O-methyl purines (2'-O), and conjugation with both cholesterol and polyethylene glycol of 40kDa (PEG40K), achieves effective prophylactic and therapeutic antiviral activity against live Omicron BA.2 variants in vivo. The study concludes by demonstrating the robustness, consistency, and potential broad utility of CRISmers using two newly identified aptamers but switching CRISPR, selection marker, and host species.

Furin as a therapeutic target in cystic fibrosis airways disease.

Clinical management of cystic fibrosis (CF) has been greatly improved by the development of small molecule modulators of the CF transmembrane conductance regulator (CFTR). These drugs help to address some of the basic genetic defects of CFTR; however, no suitable CFTR modulators exist for 10% of people with CF (PWCF). An alternative, mutation-agnostic therapeutic approach is therefore still required. In CF airways, elevated levels of the proprotein convertase furin contribute to the dysregulation of key processes that drive disease pathogenesis. Furin plays a critical role in the proteolytic activation of the epithelial sodium channel; hyperactivity of which causes airways dehydration and loss of effective mucociliary clearance. Furin is also responsible for the processing of transforming growth factor-β, which is increased in bronchoalveolar lavage fluid from PWCF and is associated with neutrophilic inflammation and reduced pulmonary function. Pathogenic substrates of furin include Pseudomonas exotoxin A, a major toxic product associated with Pseudomonas aeruginosa infection and the spike glycoprotein of severe acute respiratory syndrome coronavirus 2, the causative pathogen for coronavirus disease 2019. In this review we discuss the importance of furin substrates in the progression of CF airways disease and highlight selective furin inhibition as a therapeutic strategy to provide clinical benefit to all PWCF.

Benzimidazole compound abrogates SARS-COV-2 receptor-binding domain (RBD)/ACE2 interaction In vitro.

The development of clinically actionable pharmaceuticals against coronavirus disease (COVID-19); an infectious disease caused by the SARS-CoV-2 virus is very important for ending the pandemic. Coronavirus spike glycoprotein (GP)-Receptor Binding Domain (RBD) and its interaction with host receptor angiotensin converting enzyme 2 (ACE2) is one of the most structurally understood but therapeutically untapped aspect of COVID-19 pathogenesis. Binding interface based on previous x-ray structure of RBD/ACE2 were virtually screened to identify fragments with high-binding score from 12,000 chemical building blocks. The hit compound was subjected to fingerprint-based similarity search to identify compounds within the FDA-approved drug library containing the same core scaffold. Identified compounds were then re-docked into of RBD/ACE2. The best ranked compound was validated for RBD/ACE2 inhibition using commercial kit. Molecular dynamics simulation was conducted to provide further insight into the mechanism of inhibition. From the original 12000 chemical building blocks, benzimidazole (BAZ) scaffold was identified. Fingerprint-based similarity search of the FDA-approved drug library for BAZ-containing compounds identified 12 drugs with the benzimidazole-like substructure. When these compounds were re-docked into GP/ACE2 interface, the consensus docking identified bazedoxifene as the hit. In vitro RBD/ACE2 inhibition kinetics showed micromolar IC50 value (1.237μM) in the presence of bazedoxifene. Molecular dynamics simulation of RBD/ACE2 in the presence BAZ resulted in loss of contact and specific hydrogen-bond interaction required for RBD/ACE2 stability. Taken together, these findings identified benzimidazole scaffold as a building block for developing novel RBD/ACE2 complex inhibitor and provided mechanistic basis for the use of bazedoxifene as a repurposable drug for the treatment of COVID-19 acting at RBD/ACE2 interface.

The SARS-CoV-2 fusion domain preferentially initiates fusion in the late endosome.

SARS-CoV-2 can enter target cells via both the plasma and endosomal membranes. This ability to utilize either pathway increases the likelihood by which viral entry will succeed in delivering the viral genetic information, a vital component of the viral lifecycle. Most other viruses only utilize one or the other fusion pathway, partly due to vastly different environmental factors such as pH and membrane lipid composition. The coronavirus spike glycoprotein is responsible for facilitating viral entry by first binding to the receptor followed by membrane fusion, the latter of which is initiated by the fusion domain (FD). Improving our understanding of how the FD initiates fusion in both pathways, and whether or not one is preferred over the other, will help to elucidate the molecular mechanisms involved in the membrane fusion process of SARS-CoV-2. Through a FRET-based lipid mixing assay, the SARS-CoV-2 FD (S816-F855) displays a biphasic relationship between pH and fusion, with a pH similar to that of the late endosome (∼pH5.5-4.5) demonstrating the highest fusogenic activity. Intriguingly, when assessing the structure of the FD at pH7.4 and pH5.0 in dodecylphosphocholine, only minor conformational changes occur. This change in conformation results in the elongation of an α-helix within the fusion peptide, which alongside the fusion loop, are the two structural components of the FD that are found to be critical for full functionality of the peptide. Furthermore, the FD also favors the lipid environment of the late endosome to elicit fusion, with a specificity for the endosomal lipid BMP observed. In conclusion, the SARS-CoV-2 FD displays an α-helical extension at low pH when compared to neutral pH, that allows it to preferentially initiate fusion in a lipid and pH environment resembling that of the late endosome.

Physiological interaction of SARS-CoV-2 binding to the ACE-2 receptor

For a better knowledge of how viruses enter cells, the associations that are created between the viral glycoproteins and associated human receptors must be studied. The spike glycoprotein (S-glycoprotein) of the new coronavirus SARS-CoV-2 mediates entrance into host cells, and the cellular receptor angiotensin-converting enzyme 2 (ACE-2) has been discovered.The goal of our research was to evaluate the physiological interactions between the SARSCoV-2 and the human cell receptor ACE-2.Modifications were discovered in the S1 monomer of the receptor-binding domain of spikes using an in silico analysis. The observed modifications have a considerable impact on the interlinkage between the SARS-CoV-2 spike and ACE-2. According to the research outcome, the SARS-Cov-2 spikes proteinhas a strong attraction for the human ACE-2 receptor than the Bat-CoV spikes does. Further, the presence of two loops throughout the SARS-CoV-2 receptor binding domain (RBD) may facilitate binding to the ACE-2 (receptor)throughenhancing the quantity of atoms implicated. The reason SARS-CoV-2 binds to substrates with higher binding energies than SARS-CoV may be due to longer capping loops and changed amino acids.

Technical Data of In Silico Analysis of the Interaction of Dietary Flavonoid Compounds against Spike-Glycoprotein and Proteases of SARS-CoV-2

The spike glycoprotein (S protein), 3-chymotrypsin-like protease (3CL-Pro), and papain-like protease (PL-Pro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus are widely targeted for the discovery of therapeutic compounds against this virus. Dietary flavonoid compounds were proposed as a candidate for safe therapy for COVID-19 patients. Nevertheless, wet lab experiments for high-throughput screening of the compounds are undoubtedly time and cost consuming. This study aims to screen dietary flavonoid compounds that bind to S protein, 3CL-Pro, and PL-Pro of SARS-CoV-2. For this purpose, protein structures of the receptor-binding domain (RBD) of S protein (6M0J), 3CL-Pro (6LU7), and PL-Pro (6W9C) were retrieved from the RCSB Protein Data Bank (PDB). Twelve dietary flavonoid compounds were selected for the studies on their binding affinity to the targeted proteins by global and local docking. The docking and molecular dynamic (MD) simulations were performed using YASARA software. Out of 12 compounds, the highest binding score was observed between hesperidin against RBD S protein (−9.98 kcal/mol), 3CL-Pro (−9.43 kcal/mol), and PL-Pro (−8.89 kcal/mol) in global docking. Interestingly, MD simulation revealed that the complex between 3CL-Pro and RBD S protein has better stability than PL-Pro. This study suggests that hesperidin might have versatile inhibitory properties against several essential proteins of SARS-CoV-2. This study, nevertheless, remains to be confirmed through in vitro and in vivo assays.

NMR Experiments Provide Insights into Ligand-Binding to the SARS-CoV-2 Spike Protein Receptor-Binding Domain

We have used chemical shift perturbation (CSP) and saturation transfer difference (STD) NMR experiments to identify and characterize the binding of selected ligands to the receptor-binding domain (RBD) of the spike glycoprotein (S-protein) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We also subjected full-length S-protein to STD NMR experiments, allowing correlations with RBD-based results. CSPs reveal the binding sites for heparin and fondaparinux, and affinities were measured using CSP titrations. We then show that α-2,3-sialyllactose binds to the S-protein but not to the RBD. Finally, combined CSP and STD NMR experiments show that lifitegrast, a compound used for the treatment of dry eye, binds to the linoleic acid (LA) binding pocket with a dissociation constant in the μM range. This is an interesting finding, as lifitegrast lends itself well as a blueprint for medicinal chemistry, eventually furnishing novel entry inhibitors targeting the highly conserved LA binding site.

A bivalent SARS-CoV-2 monoclonal antibody combination does not affect the immunogenicity of a vector-based COVID-19 vaccine in macaques.

Human monoclonal antibodies (mAbs) that target the spike glycoprotein of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) offer a promising approach for the prevention and treatment of coronavirus disease 2019 (COVID-19). Given suboptimal global vaccination rates, waning immunity in vaccinated individuals, and the emergence of SARS-CoV-2 variants of concern, the use of mAbs for COVID-19 prevention may increase and may need to be administered together with vaccines in certain settings. However, it is unknown whether administration of mAbs will impact the immunogenicity of SARS-CoV-2 vaccines. Using an adenovirus vector-based SARS-CoV-2 vaccine, we show that simultaneous administration of the vaccine with SARS-CoV-2 mAbs does not diminish vaccine-induced humoral or cellular immunity in cynomolgus macaques. These results suggest that SARS-CoV-2 mAbs and viral vector-based SARS-CoV-2 vaccines can be administered together without loss of potency of either product. Additional studies will be required to evaluate co-administration of mAbs with other vaccine platforms.

ACE2-binding exposes the SARS-CoV-2 fusion peptide to broadly neutralizing coronavirus antibodies.

The coronavirus spike (S) glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus S proteins. This class of mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and beta-coronaviruses, including animal coronavirus WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses show that the fusion peptide-specific mAbs bind with different modalities to a cryptic epitope, which is hidden in prefusion stabilized S, and becomes exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.

Inhibitory potentials of ivermectin, nafamostat, and camostat on spike protein and some nonstructural proteins of SARS-CoV-2: Virtual screening approach

The search for potent oral drugs either through synthetic routes or by drug repurposing for combating the dreaded covid-19 virus is still ongoing. The coronavirus spike glycoprotein and several other non-structural proteins play crucial roles in the replication and transmission of this virus. Recent research have identified ivermectin, nafamostat, and camostat as promising drug inhibitors of SARS-CoV-2 target proteins. The broad-spectrum inhibitory action of ivermectin, nafamostat, and camostat on the spike glycoprotein and some non-structural proteins of this virus was studied in silico. The spike glycoprotein, nsp3, nsp5, nsp9, nsp10, nsp13, and nsp16 were selected for this study and were downloaded from the protein data bank. Flexible docking procedure implemented in Auto Dock Vina module was deployed for the docking procedure of the drugs with the protein receptors. Although ivermectin had the best inhibitory action on the viral spike protein and nsp10, nafamostat was identified as the compound with the best broad-spectrum activity on this virus, having the highest binding affinity values of – 9.4kcal/mol, – 7.9 Kcal/mol, – 6.1 Kcal/mol, – 8.0 Kcal/mol, and – 8.7 Kcal/mol for nsp3, nsp5, nsp9, nsp13, and nsp16 respectively. This drug, in combination with ivermectin could therefore be explored further as potential compounds that could be modified to curb the menace of the covid-19 pandemic.

Generation of zinc ion-rich surface via in situ growth of ZIF-8 particle: Microorganism immobilization onto fabric surface for prohibit hospital-acquired infection

Viruses/bacteria outbreaks have motivated us to develop a fabric that will inhibit their transmission with high potency and long-term stability. By creating a metal-ion-rich surface onto polyester (PET) fabric, a method is found to inhibit hospital-acquired infections by immobilizing microorganisms on its surface. ZIF-8 and APTES are utilized to overcome the limitations associated with non-uniform distribution, weak biomolecule interaction, and ion leaching on surfaces. Modified surfaces employing APTES enhance ZIF-8 nucleation by generating a monolayer of self-assembled amine molecules. An in-situ growth approach is then used to produce evenly distributed ZIF-8 throughout it. In comparison with pristine fabric, this large amount of zinc obtained from the modification of the fabric has a higher affinity for interacting with membranes of microorganisms, leading to a 4.55-fold increase in coronavirus spike-glycoprotein immobilization. A series of binding ability stability tests on the surface demonstrate high efficiency of immobilization, >90%, of viruses and model proteins. The immobilization capacity of the modification fabric stayed unchanged after durability testing, demonstrating its durability and stability. It has also been found that this fabric surface modification approach has maintained air/vapor transmittance and air permeability levels comparable to pristine fabrics. These results strongly advocate this developed fabric has the potential for use as an outer layer of face masks or as a medical gown to prevent hospital-acquired infections.

Structural Differences in SARS‐Cov‐2 Spike Proteins and their Effects

COVID‐19 is a highly infectious disease that mainly affects the human respiratory system. Coronavirus spike glycoproteins assist in entry and infection of cells by binding to the human ACE2 receptor. Because of this, they are the main target for antibodies and inhibitors (Walls et al., 2020).Some variants of SARS‐CoV‐2 have been classified as Variants of Concern (VOCs). One characteristic of these VOCs is an “increase in transmissibility or detrimental change in COVID‐19 epidemiology” (World Health Organization, 2021) as a result of mutations in the SARS‐CoV‐2 genome. By comparing the structures of the S proteins of SARS‐CoV‐2 (Pango lineage A) and its B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants using PyMOL, we studied the differences in the structure of the receptor binding domain (RBD) of these S proteins, explaining their increased binding affinity to the ACE2 receptor, and their consequent increased transmissibility. The structure of a protein is directly related to its function which is why we think that this investigation is crucial to understanding SARS‐CoV‐2 and its variants. We expect that these regions are important for studying possible impacts on vaccine effectiveness and specific drug targets for SARS‐CoV‐2.

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes dissociation of the S1 domains and exposure of the fusion machinery, although the molecular details of this process have yet to be observed. We report the development of bottom-up coarse-grained (CG) models consistent with cryo-electron tomography data, and the use of CG molecular dynamics simulations to investigate viral binding and S2 core exposure. We show that spike trimers cooperatively bind to multiple ACE2 dimers at virion-cell interfaces in a manner distinct from binding between soluble proteins, which processively induces S1 dissociation. We also simulate possible variant behavior using perturbed CG models, and find that ACE2-induced S1 dissociation is primarily sensitive to conformational state populations and the extent of S1/S2 cleavage, rather than ACE2 binding affinity. These simulations reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.