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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM054651-02
Application #
2701774
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1997-05-01
Project End
2000-04-30
Budget Start
1998-05-01
Budget End
1999-04-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Oklahoma State University Stillwater
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
City
Stillwater
State
OK
Country
United States
Zip Code
74078
Varma, Sameer; Jakobsson, Eric (2007) The cPLA2 C2alpha domain in solution: structure and dynamics of its Ca2+-activated and cation-free states. Biophys J 92:966-76
Varma, Sameer; Chiu, See-Wing; Jakobsson, Eric (2006) The influence of amino acid protonation states on molecular dynamics simulations of the bacterial porin OmpF. Biophys J 90:112-23
Khelashvili, George A; Pandit, Sagar A; Scott, H L (2005) Self-consistent mean-field model based on molecular dynamics: application to lipid-cholesterol bilayers. J Chem Phys 123:34910
Pandit, Sagar A; Vasudevan, S; Chiu, S W et al. (2004) Sphingomyelin-cholesterol domains in phospholipid membranes: atomistic simulation. Biophys J 87:1092-100
Malmberg, Nathan J; Varma, Sameer; Jakobsson, Eric et al. (2004) Ca2+ activation of the cPLA2 C2 domain: ordered binding of two Ca2+ ions with positive cooperativity. Biochemistry 43:16320-8
Khelashvili, George A; Scott, H L (2004) Combined Monte Carlo and molecular dynamics simulation of hydrated 18:0 sphingomyelin-cholesterol lipid bilayers. J Chem Phys 120:9841-7
Pandit, Sagar A; Jakobsson, Eric; Scott, H L (2004) Simulation of the early stages of nano-domain formation in mixed bilayers of sphingomyelin, cholesterol, and dioleylphosphatidylcholine. Biophys J 87:3312-22
Chiu, S W; Vasudevan, S; Jakobsson, Eric et al. (2003) Structure of sphingomyelin bilayers: a simulation study. Biophys J 85:3624-35
Chiu, S W; Jakobsson, Eric; Mashl, R Jay et al. (2002) Cholesterol-induced modifications in lipid bilayers: a simulation study. Biophys J 83:1842-53
Chiu, S W; Jakobsson, E; Scott, H L (2001) Combined Monte Carlo and molecular dynamics simulation of hydrated lipid-cholesterol lipid bilayers at low cholesterol concentration. Biophys J 80:1104-14