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Molecular Dynamics Simulation of Membrane Channels

Molecular Dynamics Simulation of Membrane Channels. Part III. Nanotubes Theory, Methodology. Summer School on Theoretical and Computational Biophysics June 2003, University of Illinois at Urbana-Champaign http://www.ks.uiuc.edu/training/SumSchool03/.

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Molecular Dynamics Simulation of Membrane Channels

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  1. Molecular Dynamics Simulation of Membrane Channels Part III. Nanotubes Theory, Methodology Summer School on Theoretical and Computational Biophysics June 2003, University of Illinois at Urbana-Champaign http://www.ks.uiuc.edu/training/SumSchool03/

  2. Carbon NanotubesHydrophobic channels - Perfect Models for Membrane Water Channels A balance between the size and hydrophobicity

  3. Carbon NanotubesHydrophobic channels - Perfect Models for Membrane Water Channels • Much better statistics • No need for membrane and lipid molecules

  4. Carbon NanotubesHydrophobic channels - Perfect Models for Membrane Water Channels • Much better statistics • No need for membrane and lipid molecules

  5. Water Single-files in Carbon Nanotubes Water files form polarized chains in nanotubes

  6. Water-Nanotube Interaction can be Easily Modified Hummer, et. al., Nature, 414: 188-190, 2001

  7. Calculation of Diffusion Permeability from MD 0: number of water molecules crossing the channel from the left to the right in unit time 0 can be directly obtained through equilibrium MD simulation by counting “full permeation events”

  8. Liposome Swelling Assay carbohydrate 440 nm H2O carbohydrate + H2O shrinking reswelling scattered light lipid vesicles 100 mM Ribitol GlpF is an aquaglyecroporin: both water and carbohydrate can be transported by GlpF. channel-containing proteoliposomes

  9. Chemical Potential of Water pure water pure water W W (1) (2) membrane Water flow in either direction is the same, i.e., no net flow of water.

  10. Solutes Decrease the Chemical Potential of Water Addition of an impermeable solute to one compartment drives the system out of equilibrium. dilute solution pure water W+S W (1) (2) Water establishes a net flow from compartment (2) to compartment (1). Semipermeable membrane

  11. Establishment of Osmotic Equilibrium At equilibrium, the chemical potential of any species is the same at every point in the system to which it has access. dilute solution pure water W+S W (1) (2) Semipermeable membrane

  12. Establishment of an Osmotic Equilibrium Solute molar fraction in physiological (dilute) solutions is much smaller than water molar fraction. dilute solution pure water W+S W (1) (2) Semipermeable membrane Osmotic pressure

  13. Establishment of an Osmotic Equilibrium dilute solution pure water Solute concentration (~0.1M) in physiological (dilute) solutions is much smaller than water concentration (55M). W+S W (1) (2)

  14. Osmotic Flow of Water dilute solution pure water Net flow is zero W+S W (1) (2) Volume flux of water Hydraulic permeability Osmotic permeability Molar flux of water

  15. Simulation of osmotic pressure induced water transport may be done by adding salt to one side of the membrane. NaClNa++Cl- (1) Semipermeable membrane (2) There is a small problem with this setup!

  16. Problem: The solvents on the two sides of a membrane in a conventional periodic system are connected. (1) (1) (1) (2) (2) (2) (1) (1) (1) (2) (2) (2) (1) (1) (1) (2) (2) (2)

  17. NaCl We can include more layers of membrane and water to create two compartment of water that are not in contact (1) Semipermeable membrane (2) Semipermeable membrane (1)

  18. U N I T C E L L NaCl (1) Semipermeable membrane (2) Semipermeable membrane NaCl (1)

  19. Realizing a Pressure Difference in a Periodic System membrane water membrane water membrane Fangqiang Zhu f is the force on each water molecule, for n water molecules The overall translation of the system is prevented by applying constraints or counter forces to the membrane. F. Zhu, et al., Biophys. J. 83, 154(2002).

  20. Applying a Pressure Difference Across the Membrane Applying force on all water molecules. Not a good idea!

  21. Applying a Pressure Difference Across the Membrane Applying force on bulk water only. Very good

  22. Applying a Pressure Difference Across the Membrane Applying force only on a slab of water in bulk. Excellent Pf can be calculated from these simulations

  23. Calculation of osmotic permeability of water channels Aquaporin-1 GlpF pf: 7.0 ± 0.9  10-14 cm3/s Exp: 5.4 – 11.7  10-14 cm3/s pf: 1.410-13 cm3/s

  24. Stereoselective Transport of Carbohydratesby GlpF Some stereoisomers show over tenfold difference in conductivity. stereoisomers

  25. Channel Constriction GlpF + glycerol GlpF + water red < 2.3 Å 2.3 Å > green > 3.5 Å blue > 3.5 Å HOLE2: O. Smart et al., 1995

  26. Selectivity filter

  27. Interactive Molecular Dynamics VMD NAMD

  28. Observed Induced Fit in Filter

  29. Confinement in Filter • Selection occurs in most constrained region. • Caused by the locking mechanism. RMS motion in x and y z (Å) Filter region

  30. Evidence for Stereoselectivity Ribitol Optimal hydrogen bonding and hydrophobic matching Arabitol 10 times slower

  31. Dipole Reversal in Channel • Dipole reversal pattern matches water. • Selects large molecules with flexible dipole. z (Å) cos(dipole angle with z) Dipole reversal region

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