Protein-Lipid Interactions in Lipid Droplets

Lipid droplets (LDs) are intracellular organelles whose primary function is energy storage. Known to emerge from the endoplasmic reticulum (ER) bilayer, LDs have a unique structure in which their core consists of neutral lipids, triacylglycerol (TG) or sterol ester for example, surrounded by numerous proteins and a phospholipid (PL) monolayer. Despite their importance in metabolism and metabolic diseases such as obesity, type II diabetes, or lipodystrophy, LDs have not garnered the attention that they deserve. I have used both the all-atom (AA) and coarse-grained (CG) simulations of LDs and the relevant proteins along with experimental collaboration to address a broad range of questions. The thesis will consist of exploration of five topics related to LD biology and biophysics: characterization of LD surfaces and comparison to bilayers, ER-to-LD targeting, Cytosol-to-LD targeting, biophysics of LD biogenesis, and LD biogenesis orchestrated by the ER protein seipin. The key finding of the first three parts is that LD surfaces can be distinguished from the ER bilayers due to the TG glycerol moiety exposed to the cytosol. The TG glycerol moiety exhibited at the surface can form hydrogen bonds with some protein residues (e.g., tryptophan), working as a peptide targeting mediator. I have drawn a comparable conclusion in the ER bilayer where some protein residues embedded in the hydrophobic phase (e.g., serine) preferentially attract TG, working as a TG tethering site. Finally, the CG simulations have shown TG nucleation and LD growth by increasing accessible time and length scales. The central conclusion from the CG simulations is that the transmembrane segments of seipin, critical for its function, surround an oil lens and create a unique ER-LD neck structure