Guiyab, LijonBirtles, DanielSARS-CoV-2 and its spike glycoprotein are responsible for the devastation during the COVID-19 pandemic. Using its spike glycoprotein, the virus delivers its genetic information into the targeted cells by membrane fusion in a process initiated by its fusion domain (FD). It is understood that the FD preferentially prompts fusion in an environment resembling the late endosomal membrane due to the presence of the anionic lipid, BMP, and a low pH. How this would translate to the interactions between the protein and organ-relevant lipid membranes would increase insight of viral tropism. First, the WT FD was purified via denaturing conditions, Ni-NTA affinity and finally, by size exclusion chromatography (SEC). Next, using a FRET-based lipid mixing assay, we monitored fusion activity for the WT with different cell line lipid extracts like the brain, heart, and liver to understand the interactions between the proteins and complex lipid compositions. Then, using C-Laurdan as a fluorescent probe, the lipid packing of the cell lines was monitored which determined the liver cell type with the least amount of packing. It was shown that the liver lipid composition displayed the most fusion and the lowest amount of lipid picking. Interestingly, the brain lipid compositions displayed less membrane fusion than the liver despite a higher anionic lipid concentration. In conclusion, there is an inverse relationship between lipid packing and membrane fusion mediated by the FD with a preference for lipid packing more than anionic lipid concentration for membrane fusion. This has implications for which systems in the body are more at risk and for greater caution in preventing future infection.enDepartment of Chemistry and BiochemistryCMNSCOVID-19Membrane fusionOther