Simulations now have the capability of providing insights at a sub-molecular level into structures and interactions in complex systems such as lipid membranes.
The specific aims of the proposed research are to carry-out large scale computer simulations of lipid bilayers and lipid bilayers with cholesterol. The applicant proposes to use a novel hybrid simulation method to study interactions between lipid and cholesterol molecules in hydrated lipid bilayers. The method to be used is a combination of Molecular Dynamics (MD) and """"""""smart"""""""" Monte Carlo (MC) techniques. The role of the MC part of the simulations will be to accelerate the equilibration process, both between lipid molecules, and between cholesterol molecules and lipid molecules. After lipids, cholesterol, and solvent are equilibrated satisfactorily, MD trajectories will be calculated to generate structural and temporal data for the lipid bilayer which can be compared with experiment. In the first phase of the project Dr. Scott will carry-out simulations of a bilayer of dipalmitoylphosphatidylcholine (DPPC). Next, cholesterol will be added to the DPPC bilayer and another simulation will be run. This will be repeated for 5, 15, and 30 percent cholesterol:lipid ratios. In order to move the studies closer to biologically relevant systems the applicant will carry-out simulations of bilayers of 1-palmitoyl 2-oleyl phosphatidylcloline (POPC) and dioleylphosphatidylcholine (DOPC), using the same combination of CBMC and MD. Data from these systems will be compared in detail to experimental structural and dynamical data. Next, simulations will be extended to membranes made of POPC and cholesterol, and DOPC and cholesterol, using the same ratios of cholesterol:lipid as in the DPPC-cholesterol simulations. The ultimate goal is to be able to understand in detail the physics underlying the organization of biological membranes, which include cholesterol plus several types of lipids, as well as proteins.
