Birtles, DanielSARS-CoV-2 is an extremely infectious virus, yet despite a plethora of research the viral lifecycle is still not well understood, particularly the process of membrane fusion. The traditional means by which viral glycoproteins facilitate fusion is that of the six-helix bundle, within which a short, conserved sequence known as the fusion domain (FD) initiates the process as it embeds within and perturbs the target cell membrane, in turn lowering the energetic barrier necessary to coalesce two opposing membranes. Furthermore, the highly conserved coronavirus FD is found to be available on the SARS-CoV-2 spike protein surface, which along with its integral role within the viral lifecycle makes it an ideal therapeutic target. However, limited knowledge of the exact molecular mechanism by which the SARS-COV-2 FD conducts its role within the fusion process has prevented the production of antiviral treatments. Here we describe the elucidation of key molecular details regarding how the SARS-CoV-2 FD initiates the process of membrane fusion. Firstly, the FD was found to contain a unique assembly of fusogenic regions, known as a fusion peptide (FP) and fusion loop (FL), which operate in synergy to elicit efficient fusion. This was followed by the discovery of a preference for the FD to fuse within conditions akin to the late endosomal membrane, with both pH and lipid composition significantly impacting fusion. It was found that the endosomal resident anionic lipid BMP imparts a negative impact on lipid packing within the membrane, which positively correlates with fusion. The unique mechanism by which the coronavirus FD initiates fusion was cemented when we uncovered the importance of several positively charged residues towards the FDs function. This also led to unearthing a mutant of the FD (K825A), which if found to have naturally occurred within the full spike protein, has the potential to produce a more virulent strain of SARS-CoV-2.enDissertationBiochemistryLipidsMembrane FusionSARS-CoV-2Virus