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Maikel Rheinstädter, XDL2011, June 30th, 2011 1
Maikel C. RheinstädterLaboratory for Membrane and Protein Dynamics
McMaster University, Hamilton ONand
Canadian Neutron Beam Centre, NRC, Chalk River ON
XDL2011Frontier Science with X-ray Correlation
Spectroscopies using Continuous Sources June 29-30, 2011
Cornell University, Ithaca NY
Nanobiology: Membranes and Proteins in Motion
Maikel Rheinstädter, XDL2011, June 30th, 2011 2
Maikel C. RheinstädterLaboratory for Membrane and Protein Dynamics
McMaster University, Hamilton ONand
Canadian Neutron Beam Centre, NRC, Chalk River ON
XDL2011Frontier Science with X-ray Correlation
Spectroscopies using Continuous Sources June 29-30, 2011
Cornell University, Ithaca NY
Nanobiology: Membranes and Proteins in MotionScattering experiments
outside of the comfort zone
Maikel Rheinstädter, XDL2011, June 30th, 2011 3
Challenge
OrganismOrgan
CellOrganelle
CytoskeletonFunctional Module
Biological MacromoleculeMolecule
Atom
years and meters
picoseconds and Angstroems
Maikel Rheinstädter, XDL2011, June 30th, 2011 4
Challenge
OrganismOrgan
CellOrganelle
CytoskeletonFunctional Module
Biological MacromoleculeMolecule
Atom
years and meters
picoseconds and Angstroems
Maikel Rheinstädter, XDL2011, June 30th, 2011 5
Challenge
OrganismOrgan
CellOrganelle
CytoskeletonFunctional Module
Biological MacromoleculeMolecule
Atom
years and meters
picoseconds and Angstroems
2011 J 30th00 2011 5
XPCS
Comfort Zone
Maikel Rheinstädter, XDL2011, June 30th, 2011 6
Target: Molecular Biology and Nano Medicine
Apoptosis
Lipid Membranes
Fluid Mosaic ModelSinger et al, Science (1972)
Maikel Rheinstädter, XDL2011, June 30th, 2011 7
Target: Molecular Biology and Nano Medicine
... are more than just passive barriers
Rafts
Membrane Mediated Protein InteractionsCreation of Protein Nano-environments
Alzheimer’sApoptosis
Lipid Membranes
Role of Macromolecules
cholesterol
Maikel Rheinstädter, XDL2011, June 30th, 2011 8
Overview of the LMPD
Biomedical Applications:Neurodegenerative Disorders
Apoptosis
Protein-Protein Interactions
Structure and Dynamics of Model Brain Membranes
Dynamics of Lipid/Cholesterol Systems
Nanodomains and Coexistant Phases in
Lipid Membranes
Lipid and Protein Diffusion
Drug Enhancers and Membrane Permeability
Maikel Rheinstädter, XDL2011, June 30th, 2011 9
Diffusion in Membranes and Cells –Brownian Motion or Collective Transport?
continuous diffusion with rattling in the cage
Previous ModelsRecent Model (2010)
Busch, et. al.,, JACS, (2010)
flow-like motion
Armstrong, et. al.,, submittedRheinstadter et al., PRL (2008)
Armstrong, et. al.,, Soft Matter (2010)
ballisticcontinuous?
Quasi-elastic Neutron Scattering
3Åfluid lipid membrane
Maikel Rheinstädter, XDL2011, June 30th, 2011 10
Model system: single component membrane close to the phase transition
Nanodomains - Rafts
gel phase
fluid phase
Temperaturegel fluid
coherence length �
Nanometer sized structures that fluctuate on nano-microsecond time
scales
neutron
wave packetx-ray
not been observed
Maikel Rheinstädter, XDL2011, June 30th, 2011 11
Nanodomains
DMPC DSPC
14 C atoms18 C atoms
gel
fluidfneutron coherence length
�~500 Å �~30 Å�~500 Å
Neutron diffraction
Maikel Rheinstädter, XDL2011, June 30th, 2011 12
Coherence Length
Neutron (longitudinal) coherence length: 2 EE
���
� �� �
neutron coherence length
disorderedwell ordered
good ���high spatial resolution ‘poor’ spatial resolution
Maikel Rheinstädter, XDL2011, June 30th, 2011 13
Membrane Properties
Ethanol
Hydrophillic
Cholesterol
Hydrophilic head
Hydrophobic body
Controls Membrane RigidityMD simulations, Heller et al.
Model Drug Enhancer
M. Tarek, University of Nancy
membrane fluctuationsenhances suppresses
Membrane active molecules
Maikel Rheinstädter, XDL2011, June 30th, 2011 14
Quantitative Molecular Biology – Drug Enhancer
IN12@ILL (triple-axis)
Kaye et al., PRE (2011)
MD simulations
Tr�uble 1971
DMPC/5% Ethanol
longitudinal phonon
pure lipid bilayertransversephonon
Quantitative access to membrane properties- drug development and sensor applications
Maikel Rheinstädter, XDL2011, June 30th, 2011 15
Protein-Protein Interactions
Neurotoxic senile plaques
Aggregation of amyloid proteins
Apoptosis – Programmed Cell Death
“Cancer’s self destruct button”
Alzheimer’s Disease Cancer Research
Maikel Rheinstädter, XDL2011, June 30th, 2011 16
Protein-Protein Interactions
Positive Curvature Negative Curvature
Armstrong et al., Protein and Peptide Letters (2010)
Membrane mediated elastic interactioninteraction
Maikel Rheinstädter, XDL2011, June 30th, 2011 17
inter
intra
k
k’
Protein-Protein Interactions
Neutrons and X-Rays measure protein-protein interactions in-situ under physiological conditions
Fluctuation spectrum of the 2d protein lattice
protein dynamics k=50N/m
Rheinstadter et al., Physical Review Letters (2009)
Maikel Rheinstädter, XDL2011, June 30th, 2011 18
Effect of Cholesterol on Membrane Structure
100% DMPC 0% Cholesterol90% DMPC 10% Cholesterol70% DMPC 30% Cholesterol65% DMPC 35% Cholesterol62.5% DMPC 37.5% Cholesterol60% DMPC 40% Cholesterol50% DMPC 50% Cholesterol40% DMPC 60% Cholesterol
0 10 20 30 40 50 60 70 80 90 100
Cholesterol %
Maikel Rheinstädter, XDL2011, June 30th, 2011 19
Artificial Brain Membranes
1.2
1.25
1.3
1.35
1.4
1.45
1.5
1.55
0% 10% 20% 30% 40% 50% 60% 70%
q ||
(Å-1
)
Cholesterol Percentage
Lipid Tail Peak
gas solidliquid
Mixture of 3 lipid molecules and varying levels of cholesterol
Amyloid-� protein
saturatedunsaturated
chargedcholesterol
Study protein-protein interactions in model brain membranes
Maikel Rheinstädter, XDL2011, June 30th, 2011 20
Summary
Biomedical Applications:Neurodegenerative Disorders
Apoptosisusing X-Ray (XPCS?) and
Neutron Scattering
Protein-Protein Interactions
Structure and Dynamics of Model Brain Membranes
Dynamics of Lipid/Cholesterol Systems
Nanodomains and Coexistant Phases in
Lipid Membranes
Lipid and Protein Diffusion
Drug Enhancers and Membrane Permeability
Maikel Rheinstädter, XDL2011, June 30th, 2011 21
Acknowledgements
Clare ArmstrongMartin KayeMatthew BarrettSongbo ZhengErik SandqvistNick JagoMike Moore
National Research Council of Canada
