A multiscale mechanical model for flexible spike protein-mediated SARS-CoV-2 viral entry into host cells

The COVID-19 pandemic has so far been sustained by recurrent outbreaks, largely owing to the strong contagiousness of SARS-CoV-2 (SARS2). Here, to explain its high infectivity from a mechanical viewpoint, we propose a multiscale mechanical model that links molecular-scale binding with cell-scale endocytosis in the initial stage of viral entry mediated by flexible spike (S) proteins. With three hinges in the stalk domain, SARS2-S has unanticipated orientational freedom, giving rise to a high binding affinity up to 10 times that of SARS-S binding with ACE2. Interestingly, when SARS2-S is in the "RBD-down" conformation, the affinity decreases dramatically to only one thousandth of that of SARS-S binding with ACE2, suggesting that the conformational hiding of the receptor-binding site in this flexible state could reduce its exposure to the host immune system and therapeutic antibodies. Therefore, the mechanical properties of S proteins can be exploited by the virus to enhance its recognition of host ACE2 and attachment to host cells. As S proteins bind to ACE2 receptors, the resulting S-ACE2 complexes bridge the viral and host-cell membranes and progressively accumulate at the virus-cell interface, while their deformation and loading states evolve continuously during subsequent membrane wrapping. Increasing molecular stiffness enhances the interfacial pulling force, and the resulting increase in complex stiffness further amplifies this effect. It should be noted that excessively high molecular or complex stiffness, a higher membrane bending modulus, and a larger viral size all increase the mechanical resistance to late-stage membrane wrapping. Together, these results shed light on the pivotal role of molecular flexibility in the initial stage of viral entry, showing how spike flexibility regulates both ACE2 recognition and the mechanical progression of membrane wrapping, and may provide guidance for vaccine development and drug design.