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The work presented in this thesis is an effort to gain a more holistic understanding of physicochemical regulators that drive the membrane selectivity of proteins that recognize phosphatidylserine (PS). To date, more than forty PS-binding proteins have been identified [1, 2, 3]; however, what has been largely lacking is the general approach for describing and understanding PS/protein interaction in the membrane context. While the importance of various physicochemical properties of lipid membranes in protein/lipid interactions has been more progressively recognized since the proposal of the fluid mosaic model in the early 1970s [4], most studies in the field have focused on one or two aspects of the lipid membrane, unable to account for the important synergistic effects arising from multiple factors. Strides in resolving the structure of membrane binding proteins in solution or in crystal have enabled molecular-level description of protein-lipid interactions; however, these studies tend to focus on local chemical identities at the expense of general membrane properties and their effects on protein structural arrangement. The work presented here clearly demonstrate the necessity of considering both the physical and chemical properties of the membrane in understanding lipid-protein interactions. In doing so, a generalizable approach for understanding lipid-protein interactions has emerged. First, the interaction configuration of the membrane-bound protein is proposed by combining molecular dynamics simulations with experimental methods such as x-ray reflectivity from lipid monolayers with proteins adsorbed. Then the lipid-protein interaction is decomposed into various possible interactions components, such as electrostatic and hydrophobic interactions, which are then probed using biochemical assays by varying relevant physical and chemical parameters as possible modulators for the membrane selectivity of the protein. The newly identified interaction components are treated as new dimensions in the parameter space that determines the lipid-protein interaction. Lastly, possible interplay and synergetic effects among the previously known and added parameters are further examined for a holistic view of the possible behavior of the protein within the parameter space.




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