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Modeling and Molecular Dynamics of
        Membrane Proteins
                           Emad Tajkhorshid
                  Department of Biochemistry, Center for
                  Biophysics and Computational Biology, and
                              Beckman Institute
                  University of Illinois at Urbana-Champagin
Why Do Living Cells Need Membrane
      Channels (Proteins)?
•  Living cells also need to exchange materials
   and information with the outside world

           … however, in a highly selective manner.

                                Extracellular (outside)




 Cytoplasm (inside)
Phospholipid Bilayers Are Excellent
       Materials For Cell Membranes
•     Hydrophobic interaction is the driving
      force
•     Self-assembly in water
•     Tendency to close on themselves
•     Self-sealing (a hole is unfavorable)
•     Extensive: up to millimeters
Lipid Diffusion in a Membrane




   Dlip = 10-8 cm2.s-1
 (50 Å in ~ 5 x 10-6 s)          Once in several hours!
Dwat = 2.5 x 10-5 cm2.s-1         (~ 50 Å in ~ 104 s)
                                  ~9 orders of magnitude slower
Modeling mixed lipid bilayers!     ensuring bilayer asymmetry
Fluid Mosaic Model of Membrane




 Lateral
Diffusion                                 Flip-flop
 Allowed                                 Forbidden
Ensuring the conservation of membrane asymmetric structure
Technical difficulties in Simulations of
        Biological Membranes
•  Time scale
•  Heterogeneity of biological membranes 


60 x 60 Å
Pure POPE
   5 ns
~100,000
  atoms
Coarse-grained modeling of lipids



  150 particles




   9 particles!



Also, increasing the time step by orders of magnitude.
by: J. Siewert-Jan Marrink and Alan E. Mark, University of
                 Groningen, The Netherlands
Protein/Lipid ratio

•  Pure lipid: insulation (neuronal cells)
•  Other membranes: on average 50%
•  Energy transduction membranes (75%)
   Membranes of mitocondria and chloroplast
   Purple membrane of halobacteria

•  Different functions = different protein
   composition
Protein / Lipid Composition




The purple membrane of halobacteria
Gramicidin A
 Might be very sensitive to the lipid head
group electrostatic and membrane potential
Central
 cavity
Analysis of Molecular Dynamics
     Simulations of Biomolecules
•  A very complicated arrangement of hundreds of groups
   interacting with each other
•  Where to start to look at?
•  What to analyze?
•  How much can we learn from simulations?



         It is very important to get
        acquainted with your system
Aquaporins
Membrane water channels
Tetrameric pore
Monomeric pores      Perhaps ions???
Water, glycerol, …
Functionally Important
                  Features
•  Tetrameric architecture
•  Amphipatic channel interior
•  Water and glycerol transport
•  Protons, and other ions are
   excluded
•  Conserved asparagine-proline-
   alanine residues; NPA motif
•  Characteristic half-membrane
   spanning structure




           ~100% conserved -NPA- signature sequence
N         E      NPA                  E    NPAR       C
A Semi-hydrophobic channel
Molecular Dynamics Simulations
Protein:         ~ 15,000 atoms
Lipids (POPE):   ~ 40,000 atoms
Water:           ~ 51,000 atoms
Total:           ~ 106,000 atoms




                                    NAMD, CHARMM27, PME
                                    NpT ensemble at 310 K
                                    1ns equilibration, 4ns production
                                    10 days /ns – 32-proc Linux cluster
                                    3.5 days/ns - 128 O2000 CPUs

                                   0.35 days/ns – 512 LeMieux CPUs
Protein Embedding in Membrane




Hydrophobic surface     Ring of
  of the protein      Tyr and Trp
Embedding GlpF in Membrane




77 A
112 A




        122 A
A Recipe for Membrane Protein Simulations
•  Align the protein along the z-axis (membrane normal): OPM, Orient.
•  Decide on the lipid type and generate a large enough patch
   (MEMBRANE plugin in VMD, other sources). Size, area/lipid,
   shrinking.
•  Overlay the protein with a hydrated lipid bilayer. Adjust the depth/
   height to maximize hydrophobic overlap and matching of aromatic
   side chains (Trp/Tyr) with the interfacial region
•  Remove lipids/water that overlap with the protein. Better to keep
   as many lipids as you can, so try to remove clashes if they are not
   too many by playing with the lipids. Add more water and ions to the
   two sides of the membrane (SOLVATE / AUTOIONIZE in VMD)
•  Constrain (not FIX) the protein (we are still modeling, let’s
   preserve the crystal structure; fix the lipid head groups and
   water/ion and minimize/simulate the lipid tails using a short
   simulation.

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Simulating Membrane Channels, E. Tajkhorshid, Part 1

  • 1. Modeling and Molecular Dynamics of Membrane Proteins Emad Tajkhorshid Department of Biochemistry, Center for Biophysics and Computational Biology, and Beckman Institute University of Illinois at Urbana-Champagin
  • 2. Why Do Living Cells Need Membrane Channels (Proteins)? •  Living cells also need to exchange materials and information with the outside world … however, in a highly selective manner. Extracellular (outside) Cytoplasm (inside)
  • 3. Phospholipid Bilayers Are Excellent Materials For Cell Membranes •  Hydrophobic interaction is the driving force •  Self-assembly in water •  Tendency to close on themselves •  Self-sealing (a hole is unfavorable) •  Extensive: up to millimeters
  • 4. Lipid Diffusion in a Membrane Dlip = 10-8 cm2.s-1 (50 Å in ~ 5 x 10-6 s) Once in several hours! Dwat = 2.5 x 10-5 cm2.s-1 (~ 50 Å in ~ 104 s) ~9 orders of magnitude slower Modeling mixed lipid bilayers! ensuring bilayer asymmetry
  • 5. Fluid Mosaic Model of Membrane Lateral Diffusion Flip-flop Allowed Forbidden Ensuring the conservation of membrane asymmetric structure
  • 6. Technical difficulties in Simulations of Biological Membranes •  Time scale •  Heterogeneity of biological membranes  60 x 60 Å Pure POPE 5 ns ~100,000 atoms
  • 7. Coarse-grained modeling of lipids 150 particles 9 particles! Also, increasing the time step by orders of magnitude.
  • 8. by: J. Siewert-Jan Marrink and Alan E. Mark, University of Groningen, The Netherlands
  • 9. Protein/Lipid ratio •  Pure lipid: insulation (neuronal cells) •  Other membranes: on average 50% •  Energy transduction membranes (75%) Membranes of mitocondria and chloroplast Purple membrane of halobacteria •  Different functions = different protein composition
  • 10. Protein / Lipid Composition The purple membrane of halobacteria
  • 11. Gramicidin A Might be very sensitive to the lipid head group electrostatic and membrane potential
  • 13. Analysis of Molecular Dynamics Simulations of Biomolecules •  A very complicated arrangement of hundreds of groups interacting with each other •  Where to start to look at? •  What to analyze? •  How much can we learn from simulations? It is very important to get acquainted with your system
  • 15. Tetrameric pore Monomeric pores Perhaps ions??? Water, glycerol, …
  • 16. Functionally Important Features •  Tetrameric architecture •  Amphipatic channel interior •  Water and glycerol transport •  Protons, and other ions are excluded •  Conserved asparagine-proline- alanine residues; NPA motif •  Characteristic half-membrane spanning structure ~100% conserved -NPA- signature sequence N E NPA E NPAR C
  • 18. Molecular Dynamics Simulations Protein: ~ 15,000 atoms Lipids (POPE): ~ 40,000 atoms Water: ~ 51,000 atoms Total: ~ 106,000 atoms NAMD, CHARMM27, PME NpT ensemble at 310 K 1ns equilibration, 4ns production 10 days /ns – 32-proc Linux cluster 3.5 days/ns - 128 O2000 CPUs 0.35 days/ns – 512 LeMieux CPUs
  • 19. Protein Embedding in Membrane Hydrophobic surface Ring of of the protein Tyr and Trp
  • 20. Embedding GlpF in Membrane 77 A
  • 21. 112 A 122 A
  • 22. A Recipe for Membrane Protein Simulations •  Align the protein along the z-axis (membrane normal): OPM, Orient. •  Decide on the lipid type and generate a large enough patch (MEMBRANE plugin in VMD, other sources). Size, area/lipid, shrinking. •  Overlay the protein with a hydrated lipid bilayer. Adjust the depth/ height to maximize hydrophobic overlap and matching of aromatic side chains (Trp/Tyr) with the interfacial region •  Remove lipids/water that overlap with the protein. Better to keep as many lipids as you can, so try to remove clashes if they are not too many by playing with the lipids. Add more water and ions to the two sides of the membrane (SOLVATE / AUTOIONIZE in VMD) •  Constrain (not FIX) the protein (we are still modeling, let’s preserve the crystal structure; fix the lipid head groups and water/ion and minimize/simulate the lipid tails using a short simulation.