Molecular Dynamics Simulation of Membrane Channels
Transcript of Molecular Dynamics Simulation of Membrane Channels
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Molecular Dynamics Simulationof Membrane Channels
Emad TajkhorshidBeckman Institute, UIUC
Summer School on Theoretical and Computational Biophysics
June 2004, University of Western Australia
Part I. Overview and Examples
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Molecular Dynamics Simulationof Membrane Channels
• Brief Introduction to Membrane and a few examples ofMembrane Channels
• Aquaporin Water Channels
• How to model membrane proteins in membrane
• How to analyze the data? Where to look?
• How much we can learn from simulations?
• Nanotubes and today’s tutorial
• Nanotubes as simple models for membrane water channels
• Theory of water transport and its modeling using MDsimulations
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Why Do Living Cells NeedMembranes and Membrane
Channels?• Water is the medium of life: water is themost abundant compound in livingcells/organisms, and all biochemicalreactions take place in water.
• Living cells need to isolate their interiorcompartment from the environment, a taskthat, in a water-dominated medium, can bebest done by fatty molecules.
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The Roles of Cell Membranes
Cytoplasm (inside)
Extracellular (outside)
• Conservation of materials inside the cell• Protection against undesired substances• But Access for desired substances!
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Lipid Bilayers are Excellent for CellMembranes
• Hydrophobic interaction is thedriving force for their formation
• They self-assembly in water• They tend to close on themselves• They self-seal (holes unfavorable)• They can be extensive: up to mm
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Why Do Living Cells Need MembraneChannels (Proteins)?
Cytoplasm (inside)
Extracellular (outside)
• Living cells need to exchange materials andinformation with the outside world
… however, in a highly selective manner.
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A highly selectivepermeability
barrier
Proteins in Membranes
Internalmembranes for
organelles
• As receptors, detecting signals from outside:LightOdorantTasteChemicals
HormonesNeurotransmittersDrugs
• As channels, forming gates and pumps• As generators of electric/chemical potentials
Energy storage Neurophysiology
• As energy transducersPhotosynthesisOxidative phosphorylation
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Once in several hours!(104 s)
Lipid Diffusion in Membrane
D = 1 µm2.s-1
50 Å in ~ 2.5 x 10-5 s
~9 orders of magnitudedifference
Dlip = 10-8 cm2.s-1
Dwat = 2.5 x 10-5 cm2.s-1
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Fluid Mosaic Model of Membrane
Flip-flapForbidden
LateralDiffusionAllowedEnsuring the conservation of membrane asymmetric structure
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Importance of Asymmetry
Extracellular side
Cytoplasmic side
Apart from passive transport mechanisms, all membrane proteinsfunction in a directed fashion, and their correct insertion into the
cell membrane is essential for their biological function.
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• Pure lipid: insulation (neuronal cells)• Other membranes: on average 50%• Energy transduction membranes (75%)
Membranes of mitocondria and chloroplastPurple membrane of halobacteria
• Different functions = different proteincomposition
Protein/Lipid ratio
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Protein / Lipid Composition
Light harvesting complex of purple bacteria
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Protein / Lipid Composition
The purple membrane of halobacteria
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Bilayer Permeability• Low permeability to charged and polar substances• Water is an exception: small size, lack of charge,
and its high concentration• Desolvation of ions is very costly.
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Na+
K+
++ ++
++
++
-- --
--
--
Membrane Electrical Potential
-60 mVK+
Na+
The ratio of ions is about 1 to 10 Action potential inexcitable cells
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Properties of Ion ChannelsMembrane-spanning proteinHydrophilic ion conductive pathway
Water-filledTraversing ion must lose hydration shell
Selectivecharge screening and size
Gating propertiesExist in open and closed states
Substrate is charged and the conduction can bemeasured very precisely, as opposed to waterchannels.
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Control of conduction in ion channelsGating mechanisms (open-closed transition) due to
Membrane potential change (voltage gated channels)K channels
Binding of a molecule (ligand-gated channels)Acetylcholine nicotinic receptor (Na channel)Glutamate receptor (Ca channel)
Voltage and ligand gating can co-exist
Mechanical gating (MscL)
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KcsA Potassium Channel
Under physiological conditions, the selectivityfilter of the KcsA dehydrates, transfers, andrehydrates one K+ ion every 10 ns.
PDB Feb 2003molecule of the month
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K binding sites in the selectivity filter
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Overall Mechanism of Ion Conduction
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Centralcavity
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Comparision of Potassium Channel and Water Channel
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Gramicidin Aan ion leak inside the membrane
Through dissipating the electrochemical potential ofmembranes, gramicidin A acts as an antibiotic.
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Gramicidin can form a proton wire
It also provides a membrane channel with a simplestructure which can be simulated for a long time.
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α-hemolysinchannel
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• MscL from E. coli based on homologymodel
• Sufficient water for full hydration of loopsand N-terminal helix bundle
• Constant radial force applied to residues atthe ends of M1 and M2 (16, 17, 40, 78, 79,98)
• 10 ns simulation time
Steered MD simulation
Pressure profile in membrane guided simulation
Opening of channel
Mechanosensitive Channel of Large Conductance (MscL)
J. Gullingsrud and K. Schulten, Biophys. J. 85: 2087-2099 (2003)
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Mechanosensitive Channel of Small Conductance
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~18 β-strands – found in outer membranesof G- bacteria and mitocondria
Porins: An example of β-barrelmembrane proteins
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Porins: An example of β-barrelMembrane Proteins
Usually form oligomers in the membrane.
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MaltoporinOmpF
Porins: Non-selective Pores of theOuter Membrane
periplasm
cytoplasm
extracellular
Plasma membrane
Outer membrane
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H+hν [H+]
[H+]
Cytoplasmic side
Extracellular side
hν
Bacteriorhodpsin uses sunlightand generates a transmembrane
proton gradient
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ATP synthase uses the proton gradientto produce ATP