Transcript A Molecular Dynamics Simulation Study of Sphingomyelin Bilayer

Assessing the Nature of Lipid
Raft Membranes
Perttu Niemelä
Laboratory of Physics and Helsinki Institute of Physics,
Helsinki University of Technology
GROMACS workshop
CSC, Espoo, 28 February 2007
Introduction: Lipids
Introduction: SM-SM Interactions
NH-group involved with
intermolecular h-bonding
OH-group involved with
intramolecular h-bonding
Phosphoryl oxygens
involved
with H20 hydrogen bonding
Niemelä, Hyvönen, Vattulainen (2004) Biophys J, 87:2976 – 2989
Niemelä, Hyvönen, Vattulainen (2006) Biophys J, 90:851 – 863
Introduction: CHOL-SM
Aittoniemi, Niemelä, Hyvönen, Karttunen, Vattulainen (2007) Biophys J, 92:1125-1137.
Introduction: Bilayer Phases
Liquid
disordered
Gel
Liquid
ordered
Traffic, 5 (2004) 241 - 246
Introduction: Domains
25-75 nm
75-100 nm
http://www.memphys.sdu.dk
Sphingomyelin (SM)
+ Cholesterol
http://www.memphys.sdu.dk
Phosphatidylcholine (PC)
< 25 nm
de Almeida et al, Biophys. J. 85:2406-2416 (2003)
Hancock et al, Nat Rev Mol Cell Biol 7:456-462
Introduction: Rafts in Vivo
Schuck et al (2004) J Cell Sci, 117:5955-5964.
Introduction: Rafts in Vivo
Lipid Mixtures
POPC:SM:CHOL
1:1:1
POPC:SM:CHOL
2:1:1
POPC:SM:CHOL
62:1:1
Niemelä, Ollila, Hyvönen, Karttunen, Vattulainen, PLoS Comp Biol (2007) 3:e34.
Simulation Details:
• 1024 lipids / system
• ~ 30 waters/lipid
• time-step 2 fs
• simulation length 50-100 ns
• T = 310 K (Nose-Hoover)
• p = 1 atm (Parrinello-R.)
•  = 0 (PN = PL)
• periodic boundaries
Lipids:
• Force fields previously validated
• OPLS/Berger-97 (lipid.itp)
+ GROMOS
• United atoms for CH2/CH3
• Explicit hydrogens for NH/OH
• SPC-water
Niemelä, Ollila, Hyvönen, Karttunen, Vattulainen, PLoS Comp Biol (2007) 3:e34.
Equilibration: Area per lipid
X-ray diffraction
POPC:
0.683 ± 0.015 nm2
MD-simulation
DPPC-CHOL 25%
0.48 nm2
MD-simulation
DPPC-CHOL 40%
0.43 nm2
Kucerka et al., J. Membr. Biol (2005) 208:193; Hofsäss et al., Biophys. J. (2003) 84:2192
Acyl Chain Ordering
z
Cn
Cn+1
Cn-1
1
3 cos2   1
2
1
  S mol
2
S mol 
S CD
Lateral Diffusion
POPC:PSM:CHOL
DT [10-7 cm2/s]
1:1:1
0.037 ± 0.002
2:1:1
0.08 ± 0.02
62:1:1
0.67 ± 0.06
2
1
DT  lim
t  2d
r (t )
t
Experiment PFG-NMR:
DOPC:PSM:CHOL (10% - 30% CHOL)
DT1  1.0 * 10-7 cm2/s
DT2  0.1 * 10-7 cm2/s
Filippov et al, Biophys J (2006) 90:2086.
Bilayer Thickness
POPC:PSM:CHOL
d [nm]
1:1:1
4.40 ± 0.05
2:1:1
4.29 ± 0.05
62:1:1
3.53 ± 0.05
Dd = 0.6 nm ... 0.9 nm
Membrane undulations

uund ( x, y)  uund (q)
Lindahl and Edholm., Biophys J, 79 (2000) 426 - 433
Undulatory Spectrum
yq
4
62:1:1
2:1:1
1:1:1
Niemelä, Ollila, Hyvönen, Karttunen, Vattulainen, PLoS Comp Biol (2007) 3:e34.
Elastic Properties
POPC:PSM:CHOL kc [10-20 J]
1:1:1
2:1:1
62:1:1
10 ± 2
7±2
6±2
experimental
120-170% increase,
POPC-CHOL (30-50)%
POPC:PSM:CHOL KA [10-3 N/m]
1:1:1
2700 ± 700
2:1:1
1000 ± 400
62:1:1
200 ± 100
4 to 9 * 10-20 J
experimental
1700 (SM:CHOL)
780 (PC:CHOL)
140-300 (PC)
Rawicz et al (2000) Biophys J. 79:328; Evans et al. (1990) PRL 64:2094;
Needham et al (1990) 58:997; Henriksen et al (2004) Eur Biophys J 33:732
Pressure Profiles

1 
plocal ( z ) 
  mi v i  v i   Fij  rij f ( z, zi , z j )
DV islice
i j

z
 ( z)  PN ( z)  PL ( z)
    ( z ) dz
 0
Lindahl et al. , J. Chem. Phys, 113 (2000) 3882-3893
Pressure Profiles
Niemelä, Ollila, Hyvönen, Karttunen, Vattulainen, PLoS Comp Biol (2007) 3:e34.
Lipid-Protein Interactions
R. Cantor, J. Phys. Chem. (1997) 101, 1723-1725
Lipid-Protein Interactions
z
MscL
CLOSED
OPEN
Gullingsrud et. al., Biophys J, 86 (2004) 3496-3509
Lipid-Protein Interactions
Mechanical work to create protein-shaped cavity
W   p ( z ) A( z )dz
Work to close one MscL channel in lipid bilayer:
DW  Wclosed  Wopen
Gullingsrud et. al., Biophys J, 86 (2004) 3496-3509
Lipid-Protein Interactions
Work to open MscL in different membrane environments:
POPC:PSM:CHOL
DW [kBT]
1:1:1
11  2
2:1:1
41
1:0:0
1.9  0.2
0:1:0
1.0  0.6
1:0:1 (DPPC)
1.0  0.4
Niemelä, Ollila, Hyvönen, Karttunen, Vattulainen, PLoS Comp Biol (2007) 3:e34.
Summary
• Increased SM and CHOL concentration leads to
ordered, rigid and slow bilayers
• Pressure profiles in raft and non-raft mixtures
differ -> effects on proteins?
Acknowledgements
• Other people involved:
Samuli Ollila
•
•
•
•
Jussi Aittoniemi
Marja Hyvönen Mikko Karttunen Ilpo Vattulainen
BIO-group at COMP, Helsinki Univ. of Tech.
Academy of Finland
CSC, the Finnish IT center for science
SDU supercluster (Odense, Denmark)
Peristaltic Spectrum