multiscale modeling of lipid bilayer interactions with solid substrates

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

2Science & Technology

Outline• Background

– structure of lipid bilayers– applications of supported lipid bilayers

• Modeling challenges• Atomistic modeling• Mesoscale modeling• Experimental work• Conclusions


Lipids and Bilayers


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?


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

http://www.corning.com/lifesciences/products__services/surfaces/microarray

http://www.corning.com/lifesciences/products__services/surfaces/assay


Bilayer Length & Time Scales• Bilayer dynamics vary over large length and time scales, suggesting a

multiscale approach.

Undulations:

4 Å – 0.25 mm

Bilayer Thickness: 4 nm

Area per lipid: 60 +/- 2 Å2

Stokes Radius: 2.4 nm

Length Scales

Peristaltic Modes:

1-10 ns

Undulatory Modes

0.1 ns – 0.1 ms

Lateral Diffusion

Time: 4 ps

Bond Vibrations: fs

Membrane Fusion: 1-10 s

Time Scales


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


Atomistic Model• The bilayer is composed of 72 DPPC

lipid molecules described in full atomistic detail using the CHARMM potential

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

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

ji ij

ji

ji ij

ijo

ij

ijoijononbond r

qqerR

rR

DE0

26

,

12

,, 4

2

lipid

water

substrate


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. Substrate

Water

Bila

yer

Water

Lipids

Upper leaflet

Lower leaflet


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.


Comparison with Experimental Measurements

SFA Measurements Between Substrate and Bilayer

Bilayer-Substrate Interaction Energy from Simulations

Simulations show an energy minimum at a separation of 3 to 3.5 nm

Experimental measurements show a repulsion starting around 4 nm and pullout at 3 nm separations

courtesy J. Israelachvili, UCSB


Bilayer structure near the substrate

• Lower monolayer is compressed in the vicinity of substrate

• Upper monolayer seems relatively unaffected


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 near substrate inhibit a key mechanism for lateral diffusion

Experimental valueFor free bilayers

Transverse lipid motion enables lateral diffusion

Substrate reduces transverse motion & reduces diffusivity


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


Mesoscopic Model

Membrane

Substrate

Continuum solvent

• Dissipative force– Formulation based on

Newtonian solvent viscosity

vaF ijwaterEDISSIPATIV

6

VECONSERVATIRANDOMEDISSIPATIV FFFdtvdm

ijwaterB

RANDOM

rTkDtttDF

6)'(23

• Random force– Formulation based on

fluctuation-dissipation theorem

• Conservative force– Elastic stretching of bilayer– Bending modes of bilayer– Surface interactions– Other (electrostatic, etc.)


Mesoscopic Modeling of Supported Lipid Bilayers• Continuum representation

to study large length and time scales– 1 m2, 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


x

y

0 25 50 75 1000

25

50

75

100

z: 6 6.5 7 7.5 8 8.5 9 9.5 10 10.5 11 11.5 12

x

y

0 25 50 75 1000

25

50

75

100

z: 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5 8

Mesoscopic Model Results

Substrate topography contours Membrane topography contours


Mesoscopic Model Results

Maximum and Minimum Separation

-10123456789

0 3 6 9 12 15Roughness in nm

Sepa

ratio

ns in

nm

Min_SepMax_SepMembrane

Coating Membrane spanning

MaximumSeparation

MinimumSeparation


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


AFM measurementsSpreading of Bilayer on Synthetic Substrates

AFM image & measurements

courtesy Sergiy Minko,

Clarkson University

Ref: Nanoletters, 2008, 8(3), 941-944


AFM measurementsSmoothening of membrane on rough substrates

AFM image & measurements

courtesy Sergiy Minko,

Clarkson University


Substrate roughness (nm)

Sep

arat

ion

from

subs

trate

(nm

)

0 2 4 6 8 10 12 14

0

2

4

6

8

10

Minimum SeparationMaximum Separation

Membrane conformation vs.substrate roughness

• Model shows membrane coating up to about 4-5 nm• AFM images show membrane coating 5 nm particles

Lipid membrane conformationNumerical and Experimental Results

AFM images courtesy Sergiy Minko, Clarkson U.Macroscopic model predictions

MaximumSeparation

MinimumSeparation

~ 5 nm

SUBSTRATE

BILAYER

Roiter et al. Nanoletters 8, 941 (2008)


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


Acknowledgements• Professor Sergiy Minko & his group at Clarkson U.

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


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

multiscale modeling of lipid bilayer interactions with solid substrates

Documents