Browsing by Author "Sejdiu, Besian I."

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    Elucidating the Interplay Between Lipids and Membrane Proteins Using Multiscale Computer Simulations
    (2020-07-30) Sejdiu, Besian I.; Tieleman, Dirk Peter; Ng, Kenneth Kai Sing; MacCallum, Justin L.; Lyman, Edward; Derksen, Darren J.
    Biological membranes are complex cellular structures formed by a large number of different lipid types, that also contain a variety of bound proteins, carbohydrates, and other molecules. The detailed orchestration of all these elements has been a major focus of scientific research during the last 5 decades. Computer-based methods, such as molecular dynamics (MD) simulations, have proven to be a valuable approach in addressing many of the details of lipid organization and membrane protein activity. I used MD simulations at both atomistic and coarse-grained level of detail to study the number of way lipids and proteins interact and their possible functional ramifications. In part of my work, I studied the interaction of G Protein-Coupled Receptors (GPCRs) with lipids at a family-wide level. Plenty of other computational studies had shown specific lipid-protein interactions for a handful of GPCRs but with quite different outcomes on their number, location, and lipid identity. In my work, I simulated 28 different GPCR structures and showed that they are distinguished by a unique interaction profile with membrane lipids. I provided a comprehensive analysis of simulation results with available crystallographic data. I also studied the lipid-protein interaction profile of AMPA receptors and cyclooxygenases (mainly COX-1), showing that they both form specific interactions with lipids, but do so in a quite different fashion. AMPA receptors interact specifically with diacylglycerol lipids, whereas COX-1 enzymes do so indiscriminately with glycerophospholipids, cholesterol, and fatty acids, but at different levels of interaction strength. Using atomistic simulations, we show the binding pathway of arachidonic acid to COX-1 and identify a series of arginine residues that guide it toward the hydrophobic cavity of the enzyme. As part of my work, I also developed a webserver that automates the analysis and visualization of lipid-protein interactions from MD simulations allowing for the creation of automated pipelines to study lipid-protein interactions in the future. Lastly, I provide a short review of some of the main challenges facing the field along with possible solutions going forward. My work expands our understanding of lipid-protein interactions.