One of the most striking features of the Covid-19 outbreak is the enormous variation in individual susceptibility to the virus. Coronaviruses gain access to the host cell by binding host membrane proteins via the viral membrane envelope spike protein (S-protein). They represent a Trojan horse that allows infection after interaction of the S-protein with the host cell.

One goal of this proposal is to characterize the interactions of the S-protein with genetic variants of host membrane proteins, both structurally and biophysically. The knowledge gained will allow us to better understand why individuals respond so differently to the virus. This may allow classification of at-risk patients and pave the way for personalized therapies.

Since the lipid composition of the host cell depends on the tissue as well as on the age, dietary habits and previous diseases of the host, studies on the dependence of the membrane binding of the spike protein on the lipid composition could provide insights into why certain populations are more susceptible to infection with SARS-CoV-2, regardless of their genetic background. Therefore, the interactions of the S-protein with model membranes will be investigated to analyze the influence of lipid composition on protein-membrane interactions.

Key Aspects
The work in the project has three interwoven key aspects: (A) the identification, cataloging, and mapping of the genomic variants of the ACE2-receptor and the SARS-CoV-2 S-protein; (B) the study of the structure of biomolecular complexes formed by the SARS-CoV-2 S-protein and the ACE2-receptors; and (C) an analysis of the interactions of the spike fusion peptide with model membranes to determine the influence of the lipid composition of the membranes.