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    Langevin dynamics simulations of charged model phosphatidylinositol lipids in the presence of diffusion barriers: toward an atomic level understanding of corralling of PIP2 by protein fences in biological membranes.

    BMC Biophys 2014 26;7:13. Epub 2014 Nov 26.
    Laboratory of Computational Biology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD USA.
    Background: The polyvalent acidic lipid phosphatidylinositol, 4,5-bisphosphate (PIP2) is important for many cellular functions. It has been suggested that different pools of PIP2 exist in the cytoplasmic leaflet of the plasma membrane, and that such pooling could play a role in the regulation of PIP2. The mechanism of fencing, however, is not understood.

    Results: This study presents the results of Langevin dynamics simulations of PIP2 to elucidate some of the molecular level considerations that must be applied to models for fencing. For each simulation, a pool of PIP2 (modeled as charged spheres) was placed in containments with boundaries modeled as a single row of rods (steric or electrostatic) or rigid protein filaments. It is shown that even a small gap (20 Å, which is 1.85 times larger than the diameter of a PIP2 sphere) leads to poor steric blocking, and that electrostatic blockage is only effective at very high charge density. Filaments of human septin, yeast septin, and actin also failed to provide adequate blockage when placed on the membrane surface. The two septins do provide high blockage consistent with experiment and with phenomenological considerations of permeability when they are buried 9 Å and 12 Å below the membrane surface, respectively. In contrast, burial does not improve blockage by the "arch-shaped" actin filaments. Free energy estimates using implicit membrane-solvent models indicate that burial of the septins to about 10 Å can be achieved without penetration of charged residues into the hydrophobic region of the membrane.

    Conclusions: These results imply that a functioning fence assembled from protein filaments must either be buried well below the membrane surface, have more than a single row, or contain additional components that fill small gaps in the filaments.
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