Computermodelle von Spike-ACE2-Wechselwirkungen zur Entwicklung von the-rapeutischen Proteine

The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. In this project we studied the interaction between the virus and potentially infected cells at a molecular level.

In a first step, the SARS-CoV-2 Spike protein interacts with the angiotensin converting enzyme 2 (ACE2) at the surface of human cells. Viruses heavily use glycosylation to avoid the immune system. By covering protein surfaces with glycans that are produced by the host-cell, the immune system does not recognize the viral proteins as invading systems. Both Spike and ACE2 are glycosylated proteins. In the available structures, the glycans were not, or only partially, resolved. We have created computer models of the full Spike-ACE2 complex, with complete N-glycosylation included.

Using molecular dynamics simulations we studied the interaction between the two and found that glycans on ACE2 may actually inhibit a tighter binding of Spike to ACE2. This is a highly relevant finding in the development of human recombinant soluble ACE2, which can act as a decoy receptor to block the viral Spike (hrsACE2; currently in phase 2b clinical trials by Apeiron Biologics). The predictions following from the computer models, were subsequently tested in experiments. Indeed, removal of glycans on ACE2 lead to tighter binding between the RBD and ACE2, and also to a more pronounced inhibition of viral infection in cell-based systems. These findings make decoy receptors more effective in competing with cellular ACE2.