Protein targeting to membranes is important for proper function in the cell. Proteins need to identify the proper biological membranes within the cell and do so through a variety of membrane bound domains, including amphipathic helices and membrane hairpin domains. In this thesis, work is presented that addresses these membrane-targeting mechanisms. Specifically, the mechanisms of protein targeting to lipid droplets (LD) are identified. LD membranes contain larger and more frequent packing defects compared to bilayer membranes due to the intercalation of neutral lipids in the phospholipid tails. This increased space in LD membranes allows for more stable insertion of all amino acids. LD membranes are therefore more promiscuous and allow a larger variety of amphipathic helices to bind. Additionally, LD proteins targeting from the ER undergo conformational change upon relocalization to LDs due to the switch from a phospholipid bilayer to a phospholipid monolayer and neutral lipid core. LD proteins that relocalize from the ER contain a concentration of large hydrophobic residues near the bilayer midplane. These residues are shifted in LD membranes towards the carbonyl region in the phospholipid tails, a more packing defect enriched area. Finally, a new method coarse-graining method is presented that allows one to accurately model the folding process of proteins using a multistate approach. This multi-configurational coarse-graining method is demonstrated for helix folding in water and can be extended to study amphipathic helix binding and folding on biomembranes.




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