Modeling of the SARS-CoV-2 Spike protein and its interaction with ACE2

The initial interaction of SARS-CoV-2 with human cells results from a protein-protein interaction between the SARS-CoV-2 Spike protein and the human ACE2 receptor. Promising novel pharmaceutics are based on solubilized versions of the ACE2 receptor, potentially blocking the virus proteins and hindering an interaction with human ACE2 present on the cells. Atomistic models of the Spike proteins and the ACE2 receptor are available, with the glycan structures reduced to the first 1-2 sugar residues. We have created a complete model of the Spike-ACE2 interaction, with full glycosylation. The model confirms that the glycans can play a significant role in the interaction. In particular, there is evidence that removal of the N90 glycan strengthens the interaction. This offers possibilities to engineer the therapeutic proteins to show stronger interactions with Spike and therefore be more effective. We will create computer models of Spike – ACE2 interactions with different variants of ACE2. This includes species-specific variations (mouse ACE2 does not interact with Spike), naturally occurring genetic modifications, and alternative therapeutic formats.