Abstract
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.
Highlights
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
Structures resolved using cryo-electron microscopy combined with docking have shown that angiotensin-converting enzyme 2 (ACE2)-receptor binding domain (RBD) binding requires spike trimers to be open, and that two spike trimers can be accommodated on one ACE2 dimer[9]
Cryo-EM structures have shown that up to three soluble ACE2 monomers can bind to the same spike trimer, which may result in the exposure of the S2 trimeric core[10]; soluble ACE2 trimers were recently demonstrated as an effective inhibitor of SARS-CoV-211
Summary
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. We 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. Cryo-EM structures have shown that up to three soluble ACE2 monomers can bind to the same spike trimer, which may result in the exposure of the S2 trimeric core[10]; soluble ACE2 trimers were recently demonstrated as an effective inhibitor of SARS-CoV-211 Both modalities are potentially important for viral avidity and require that the RBDs throughout the spike trimer stochastically open[6,7], it is unclear if RBDs open independently or cooperatively due to ACE2 interactions. At present, such insights are difficult to obtain from experiments alone[18]
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