This project focuses on the study of membranes, proteins and carbohydrates by molecular dynamics computer simulation. Progress is reported under each Aim listed above Aim 1. Understand Model Membranes. A unified treatment of curvature of membranes has been developed wherein a lipid mixture is simulated both in the inverse hexagonal phases (where experimental data are directly available) and the lamellar phase (as present in cell membranes). Simulations on POPC and POPE demonstrated the the that bending free energy is the same for the two phases of each lipids, differences between the two lipids, and confirmed experimental assumptions regarding the location of the pivotal plane. A paper describing these results has been submitted for publication. Evaluation the curvature and bending free energy for membranes containing cardiolipin, polyunsaturated lipids, and membrane active peptides is underway. The Saffman-Delbrck (SD) theory was extended to evaluate diffusion constants of dimers and trimers in lipid membranes using velocity response functions. The results for different characteristic lengths are compared with recent experiments and molecular dynamics simulation, and inconsistencies in the SD model are demonstrated. It is likely that the SD assumption that the bilayer is a homogenous slab with a single viscosity must be replaced by a more complex description. A paper described the work has been submitted for publication.
Aim 2. Develop Simulation Methodology. The correct treatment of the inverse hex phase noted above required development of a new algorithm for evaluating the pressure in the interior of a curved interface. A paper describing the theory and tests on simple systems (pure water and a water tube in octane) has been submitted for publication. Simulations of lipid bilayers using newly developed force field parameters for phospatidylserine, cardiolipin, and phosphoinositols in NaCl have been shown to agree well with experiment. Papers describing each system will be submitted shortly. This work greatly expands the reach of membrane simulations. A web-based version of Grand Canonical Monte Carlo/Brownian Dynamics (CCMC/BD) for the study of ion channels was published (3). This was the cover article for the January 30, 2012 issue (Vol 33, number 3) of the Journal of Computational Chemistry.
Aim 3. Simulate Complex Membranes Four papers associated with this Aim were published during this reporting period. A combined experimental and simulation study showed definitively that corralling by a fence is the underlying mechanism for pooling of PIP2 on the surface of nascent phagosomes (1). The nature of the fence remains unknown, though simulations and experiments ruled out actin. Subsequent simulations indicate that septin can retard PIP2 diffusion, but only when inserted at least 15 Angstroms in the membrane. MD simulations of gramiciden A (gA) in membranes composed of lipids with different chain lengths (DLPC, DMPC,DOPC and POPC) show that the channel structure varied little with changes in hydrophobic mismatch, and that the lipid bilayer adapts to the bilayer-spanning channel to minimize the exposure of hydrophobic residues (2). The lipid behavior in the first shell around gA dimers is more complex than predicted from a simple (continuum) mismatch model,highlighting the importance of explicit simulation. Using the methods described in Aims 1 and 2, the free energies of bending for these and related systems are being evaluated. MD simulations and measurements using fluorescence and neutron reflectometry consistently indicated that the N-terminal fragment of alpha-synuclein resides in a broad low-energy region 8.5 to 14.5 Ang from the membrane center (4). Ongoing studies involving the antimicrobial peptides Pisciden 1 and Pisciden 3 highlight the sensitivity of the depth of insertion of membrane active peptides with lipid composition. MD simulations and X-ray scattering determined that bioflavinoids genistein and daidzein in DOPC bilayers lie just below the membrane/water interface, nearly parallel to the plane of the bilayer with their carbonyl groups preferentially pointed toward the proximal surface (5). Measurements of bending modulus and simulation results for area compressibility modulus indicate that both bioflavinoids soften bilayers. This was the cover article for the April 5, 2012 issue (Vol 116, number 13) of the Journal of Physical Chemistry B.
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