Hello, A yearly allocation for the LCRC cluster has been requested with the following updated information: Submitter/PI: Ursula Perez Salas Project Name: lipidmovement Division: MSD Project title: Curvature Effect on the Movement of Lipids Within and Between Membranes Associated funding: LDRD Other Systems: UIC extreme cluster Science: This project uses Molecular Dynamics simulations to investigate the diffusion of lipids, specifically cholesterol, in curved lipid (DPPC) membranes. We will calculate the free energy profile of extraction as well as flip-flop in a curved lipid membrane, i.e. a vesicle. The results will be compared to those obtained from MD simulations on planar membranes, which agree with experimental data of planar membranes (neutron reflectivity) but disagree substantially from data on highly curved lipid vesicles (small angle scattering). Scattering experiments appear to show that the flip-flop rates are fast in flat membranes and slow in the curved membranes. Thus curvature is expected to affect the transfer rate of lipids into the membrane as well as its movement across lipid leaflets. The results will provide an atomic-level explanation for the kinetic rates obtained in small angle neutron scattering experiments. The movement of lipids within membranes (flip-flop) together with the exchange between membranes under physiological conditions allows the creation of asymmetric distributions of lipids across cellular membranes. Further, the location of lipids and their rate of exchange have important biological consequences, especially for lipids involved in cellular signaling. Therefore decoding the underlying mechanisms that control lipid transfer between and within lipid membranes is critical for understanding lipid homeostasis in the cell as well as the metabolic pathways that sustain it. The proposed research seeks to identify key physical membrane properties, specifically curvature, which govern both exchange and flip-flop of lipids in membranes. Project description: We have used coarse-grained simulations utilizing the MARTINI force field to create a unilamellar lipid vesicle, 30nm in diameter, solvated in water consisting of 1M particles. This vesicle size is similar to those used in neutron scattering experiments to which we want to compare the simulations results. In our previous project we calculated the free energy profile of a single lipid (DPPC) across a flat bilayer as well as a vesicle (curved membrane) using the umbrella sampling technique. Our preliminary results show an increase in the energy barrier of lipid flip-flop across the membrane in the curved case compared to the flat bilayer which indicate slower flip-flop rates. We now plan to add cholesterol to the system at extremely low and high concentrations, which will eventually partition into the lipid (DPPC) vesicle. We will then calculate the free energy profile for cholesterol across the bilayer at each concentration and also comparing to the case of a flat membrane. In the Umbrella sampling technique the phase space is divided into many small regions, which are sampled independently and then combined using the Weighted Histogram Analysis method to provide a single energy profile. The umbrella sampling technique allows us to run many short simulations in parallel which are then combined through post-processing. We will use the molecular dynamics program NAMD, which is developed at University of Illinois at Urbana-Champaign and is freely available for download (http://www.ks.uiuc.edu/Research/namd/). NAMD is highly parallel and scales efficiently with the number of particles in the system. Our previous simulations on the Fusion cluster has shown a benchmark of 7ms/timestep on 512 cores. Using a time step of 10fs, we estimate that the proposed calculations require approximately 5 microseconds of simulation requiring a total of 495,000 core-hours. Industry partnership: Project URL: Current FY Hours Used: undetermined amount New FY Requested allocation: 496000 Q1: 124000 Q2: 124000 Q3: 124000 Q4: 124000 Justification: Storage requirements: Thank You, The LCRC Accounts System