The general goals of the proposed research are to utilize very large scale computer simulations to study lipid bilayers and lipid bilayers with cholesterol or membrane proteins, at the atomic level. We propose to apply our previously developed hybrid simulation method. to study interactions between lipids, between lipids and cholesterol, and between lipids and the KcsA potassium channel. We also propose to study permeation and gating in the KcsA channel in a lipid bilayer. All simulations will utilize system length and time scales that are about an order of magnitude larger than present simulations. By these means we will reduce finite size effects, and sample a much larger ensemble of lipid-cholesterol and lipid-KcsA microenvironments. At the same time we will extend our simulations to systems of increasing biological significance.
The Aims of the project are: (1) Set up and run 2-4 nanosecond (ns) simulations of large, fully hydrated, bilayers of lipids (POPC and DPPC) plus cholesterol at lipid: cholesterol ratios of 3:1 and 4:1. (2) Carry out simulations of 3:1 POPC:chol and DPPC:chol for smaller systems than above (648 membrane molecules plus excess water), but for over 12 ns. (3) Carry out potential-of-mean-force molecular dynamics calculations to characterize gating and ion permeation in KcsA channels embedded a large, fully hydrated, lipid bilayer. (4) Carry out 2-4 ns simulations of large (1600 lipids) bilayers of sphingomyelin (SGML) in excess water. (5) Extend the simulations of Aim 4 to include cholesterol in SGML membranes. The results of this work will be significant both for understanding the interaction of cholesterol and proteins with biologically important lipids in membranes, and the consequent implications for membrane lateral organization. Our results should also be important for developing simulation methodology for dealing with heterogeneous membranes of biological significance.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM054651-05A1
Application #
6328182
Study Section
Biophysical Chemistry Study Section (BBCB)
Program Officer
Chin, Jean
Project Start
1997-05-01
Project End
2005-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
5
Fiscal Year
2001
Total Cost
$265,340
Indirect Cost
Name
Illinois Institute of Technology
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60616
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