heine-david-hpcc by wanghonghx

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									                                            Science &
                                            Technology

Multiscale Modeling of Lipid Bilayer
Interactions with Solid Substrates

David R. Heine, Aravind R. Rammohan, and
Jitendra Balakrishnan

October 23rd, 2008

RPI High Performance Computing Conference
Outline
• Background
    – structure of lipid bilayers
    – applications of supported lipid bilayers
•   Modeling challenges
•   Atomistic modeling
•   Mesoscale modeling
•   Experimental work
•   Conclusions




              Science & Technology               2
Lipids and Bilayers




          Science & Technology   3
Technological Relevance of Supported Lipid Bilayers
• SLBs are important for various biotech applications
   – Biological research
      •   Model systems to study the properties of cell membranes
      •   Stable, immobilized base for research on membrane moieties
      •   Biosensors for the activity of various biological species
      •   Cell attachment surfaces
   – Pharmaceutical research
      • Investigation of membrane receptor drug targets
      • Membrane microarrays: High throughput screening for drug
        discovery
   – How does bilayer-substrate interaction affect bilayer behavior?



               Science & Technology                                    4
Supported Lipid Bilayers at Corning
• Applications: Membrane-protein
  microarrays for pharmaceutical
  drug discovery
• Substrate texture is important in
  the adhesion and conformation of
  bilayers on the surface
  – Crucial for the biological
    functionality of bilayers
• Objective: Quantify the effect of
  substrate topography and chemical
  composition on bilayer
  conformation and dynamics
             Science & Technology     5
Bilayer Length & Time Scales
• Bilayer dynamics vary over large length and time scales, suggesting a
  multiscale approach.
                                                            Time Scales
    Length Scales
                                                          Bond Vibrations: fs

        Stokes Radius: 2.4 nm
                                                            Lateral Diffusion
                                                               Time: 4 ps

                        Bilayer Thickness: 4 nm
                                                            Peristaltic Modes:
                        Area per lipid: 60 +/- 2   Å2
                                                                 1-10 ns


                                                            Undulatory Modes
                           Undulations:
                                                             0.1 ns – 0.1 ms
                           4 Å – 0.25 mm
                                                        Membrane Fusion: 1-10 s
              Science & Technology                                                6
Multiscale Approach
• Atomistic model
  – capture local structure and short term dynamics
• Mesoscale model
  – capture longer length and time scales
  – sufficient to look at interaction with rough surfaces




             Science & Technology                           7
Atomistic Model
• The bilayer is composed of 72 DPPC
  lipid molecules described in full atomistic               lipid
  detail using the CHARMM potential

• Water uses the flexible SPC model to          water
  allow for bond angle variations near the
  substrate

• The substrate is the [100] face of a-
  quartz with lateral dimensions of 49 x 49
  Å described by the ClayFF potential
                                                substrate




               Science & Technology                                 8
Simulation Technique
• System is periodic in x and y
  directions with a repulsive wall above      Water
  the water surface in the z direction
                                              Lipids

• NVT ensemble must be used since
                                              Upper
  pressure control is prohibited by the




                                                        Bilayer
                                              leaflet
  solid substrate
                                              Lower
                                              leaflet
• Temperature is maintained at 323K
  with a Nose-Hoover thermostat

• Total energy and force on the bilayer       Water
  are extracted during the simulation.

  Heine et al. Molecular Simulations, 2007,   Substrate
  33(4-5), pp.391-397.

                   Science & Technology                    9
Simulation Technique
• System is periodic in x and y
  directions with a repulsive wall above
  the water surface in the z direction

• NVT ensemble must be used since
  pressure control is prohibited by the
  solid substrate

• Temperature is maintained at 323K
  with a Nose-Hoover thermostat

• Total energy and force on the bilayer
  are extracted during the simulation.

  Heine et al. Molecular Simulations, 2007,
  33(4-5), pp.391-397.

                   Science & Technology       10
Comparison with Experimental Measurements
                                             Bilayer-Substrate Interaction
                                               Energy from Simulations
   Simulations show an energy
   minimum at a separation of 3 to
   3.5 nm

   SFA Measurements Between
      Substrate and Bilayer




                                      Experimental measurements
                                      show a repulsion starting around
                                      4 nm and pullout at 3 nm
                                      separations
  courtesy J. Israelachvili, UCSB

               Science & Technology                                          11
Bilayer structure near the substrate




  • Lower monolayer is compressed
    in the vicinity of substrate
  • Upper monolayer seems
    relatively unaffected
            Science & Technology       12
Effect of substrate on lateral lipid diffusion
• Reduction in lateral
  diffusivity observed,
  compared to free bilayers
   – Bulk simulations
     match diffusivity of
     free bilayers

• Suppression of
  transverse fluctuations            Transverse lipid     Substrate reduces
  near substrate inhibit a           motion enables      transverse motion &
                                                              Experimental value
  key mechanism for                  lateral diffusion         For diffusivity
                                                           reducesfree bilayers
  lateral diffusion



              Science & Technology                                                 13
Atomistic Simulation Results
• MD simulations show bilayer-substrate equilibrium
  separation of 3 – 3.5 nm, in agreement with SFA
  experiments

• Lateral diffusion of the lipid head groups decreases as the
  bilayer approaches the substrate

• Suppression of transverse fluctuations may be responsible
  for reduced lateral diffusion




            Science & Technology                                14
  Mesoscopic Model



• Dissipative force                     • Conservative force
   – Formulation based on                  – Elastic stretching of bilayer
     Newtonian solvent                     – Bending modes of bilayer
     viscosity                             – Surface interactions
                                           – Other (electrostatic, etc.)
• Random force                                                    Membrane
   – Formulation based on
     fluctuation-dissipation
     theorem                                     Continuum solvent



                                                          Substrate
                 Science & Technology                                        15
Mesoscopic Modeling of Supported Lipid Bilayers
• Continuum representation
  to study large length and
  time scales
   – 1 mm2, 1 ms


• Allows study of bilayer
  behavior on textured
  substrates

• Dynamic model that
  includes effect of solvent
  and environment                   All dimensions in nanometers
                                           z axis not to scale

             Science & Technology                                  16
Mesoscopic Model Results




   Substrate topography contours    Membrane topography contours
             Science & Technology                                  17
Mesoscopic Model Results



                                Membrane
                                 Coating   Membrane
                                           spanning

                                                                   Maximum
                                                                   Separation


                                                       Minimum
                                                      Separation




         Science & Technology                                                   18
Mesoscopic Model Results
• Allows study of bilayer on micron and microsecond scales

• Minimum surface roughness of 4-5 nm required for
  membrane spanning conformation

• Spanning configuration important for maintaining bilayer
  mobility




            Science & Technology                             19
AFM measurements
Spreading of Bilayer on Synthetic Substrates




                                                                 AFM image &
                                                                 measurements
                                                                   courtesy
                                                                 Sergiy Minko,
                                                                   Clarkson
                                                                  University

                                   Ref: Nanoletters, 2008, 8(3), 941-944
            Science & Technology                                                 20
AFM measurements
Smoothening of membrane on rough substrates




                                              AFM image &
                                              measurements
                                                courtesy
                                              Sergiy Minko,
                                                Clarkson
                                               University



           Science & Technology                               21
Lipid membrane conformation
Numerical and Experimental Results
     Macroscopic model predictions            AFM images courtesy Sergiy Minko, Clarkson U.



                                             BILAYER



                                Maximum
                                Separation        ~ 5 nm

                    Minimum
                   Separation


                                             SUBSTRATE

                                             Roiter et al. Nanoletters 8, 941 (2008)
• Model shows membrane coating up to about 4-5 nm
• AFM images show membrane coating 5 nm particles

               Science & Technology                                                     22
Conclusions
• MD simulations show bilayer-substrate separation of 3 – 3.5 nm, in agreement
  with SFA experiments

• MD simulations show reduced lateral diffusion in lipids as the bilayer approaches
  the substrate

• Mesoscopic model shows membranes coat particles up to 4 – 5 nm in diameter,
  in agreement with AFM observations

• Larger surface features are needed to achieve separation between bilayer and
  substrate

• High-performance computing has opened up new approaches for understanding
  biomolecule-substrate interactions, which aids design

• There is still plenty of room to grow as these models are still restricted in terms of
  size, timescale, and complexity
                 Science & Technology                                                      23
Acknowledgements
• Professor Sergiy Minko & his group at Clarkson U.

• Professor Jacob Israelachvili & his group at U. C. Santa
  Barbara




            Science & Technology                             24
Lipid Behavior on Nanoparticles
• Bilayer conforms to
  Nanoparticles < 1.2 nm

• Bilayer undergoes
  structural re-
  arrangement involving
  formation of holes
  between 1.2 – 22 nm

• Beyond 22 nm bilayer
  envelops the particle

                                   Ref: Nanoletters, 2008, 8(3), 941-944
            Science & Technology                                           26

								
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