The membrane fusion mechanism of SARS-CoV-2 offers an attractive target for antiviral drug development. However, the process remains to be fully understood at the cellular level, beyond the known initial binding of the crown-like trimeric spike glycoproteins of SARS-CoV-2 to the receptor angiotensin-converting enzyme 2 (ACE-2) on the permissive host cellular membrane. In this study, we computationally build super-complexes of spike trimer/ACE-2 dimers based on the molecular structures of the ACE-2/neutral amino acid transporter B(0)AT heterodimer. We determine the potential effects of membrane geometry on the enzymatic activity of ACE-2 and on the viral fusion process. We find that binding one ACE-2 dimer with two spike trimers retains the tethered coronaviruses in a non-invasive state, locking the peptidase domain of ACE-2 in a closed conformation unfavorable for its peptidase activity. Furthermore, we find that binding three ACE-2 dimers per spike trimer is essential to open the central pore as necessary for triggering productive membrane fusion by elongation of the central stalk. The reported insights are thus particularly valuable for targeting the membrane fusion mechanism at the molecular level.

Computational insights into the membrane fusion mechanism of SARS-CoV-2 at the cellular level

ACS Spring Meeting 2021

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