Driving Force of Lipid Raft Formation: A Monte Carlo Simulation of Raft Mixture Phase Diagrams

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Lipid raft domains are thought to be involved in important cell functions. It has been suggested that its formation is purely due to lipid-lipid interaction, which is supported by recent experimental evidence that the liquid-ordered domains can be reproduced on synthetic liposomes containing unsaturated phosphatidylcholine (PC), sphingomyelin (SM), and cholesterol. A crucial question is what is the driving force for lipid raft formation? Current hypotheses include a strong van der Waals attraction between cholesterol and the long saturated acyl chain of sphingomyelin, hydrogen bonding between cholesterol and sphingolipids and an entropy effect of hydrocarbon chains. In this project, Monte Carlo simulations will be used to reproduce the experimental phase diagram of DOPC/SM/cholesterol mixtures, through which the hypotheses will be tested and the key molecular interactions will be identified. Specifically, the PI will use both pairwise and multibody interactions to build explicit molecular interaction model for each hypothesis and quantitatively test these hypotheses by simulating lipid raft phase in PC/SM/cholesterol mixtures. Experimental values on composition and amount of coexisting phases and the magnitude of interaction will be used to judge the hypotheses. Entire phase diagrams of the PC/SM/cholesterol system will be constructed by free energy simulations to quantitatively identify the headgroup and acyl chain contributions using experimental phase diagrams of different lipid mixture systems. The goal is to search for a clear physical model and a set of interaction parameters that can closely reproduce the experimental phase diagram. Lipid rafts are cell membrane domains containing membrane proteins, phosphatidylcholine, sphingomyelin, and cholesterol. These domains are thought to be very important to cell functions. This research is the first large-scale theoretical modeling effort to understand the mechanism of its formation. The success of the project would be a significant contribution to the fields of biomembrane and lipid biophysics, and would stimulate more experimental and molecular dynamics simulation studies. Students involved in the project will receive lecture and hands-on training in lipid biophysics, computer simulation, and parallel computing using Beowulf cluster. This modeling project combining with the ongoing experimental research program would attract more students to Texas Tech University, which has a large minority student population and is geographically underrepresented.