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Modelling of Protein-Lipid Interactions
Lea Thøgersen
PUMPKIN Opfølgningsmøde
February 24, 2009
Outline
A PUMPKIN Postdoc
Work in Progress
Future Work
A PUMPKIN Postdoc Bachelor in Chemistry and Molecular Biology PhD in Theoretical Chemistry (2005)
Method development Software development Small molecules
2Y Postdoc from LundbeckFonden (2005-8) Bioinformatics Research Center (BiRC) Membrane Proteins – new insight via MD simulations Antimicrobial peptides – interaction with lipid bilayer.
Collaboration with NMR (inSPIN)
PUMPKIN Postdoc since August 2008 Pumps are fascinating systems, with all kinds of interesting
modelling aspects, which have not yet been touched Fantastic setup of extraordinary insights and years of experience
Membrane Proteins
Protein-Lipid Interactions
Lipid is the new water
Annular shell (like solvation shell) Generally not structure specific
Non-annular lipids Acting as co-factors Affect function Potentially structure specific
SERCA – Lipid Interaction
Sarcoplasmic reticulum Ca2+ ATPase Membrane position First time annular lipids observed in high-res X-ray Thapsigargin – lipid mimicking?
SR membrane Low concentrations of sterols and sphingolipids
X-ray membrane Native Detergent C12E8, lipid:detergent 7:16
All-Atom MD Study
POPC
E2 form (Thapsigargin-like inhibitor removed from the structure).
No Ca2+ ions, 0.2M K++Cl-
DOPCDOPC
DMPC
+2 SAPC
-2 MPPC
O
O
O
O
O
O
O
OO
O
MD X-ray
POPC – TRP shown
X-ray lipids in orange
SERCA Position in Bilayer
DMPC MPPC POPC DOPC SAPC
A.G. Lee, Biochimica et Biophysica Acta 1612 (2003) 1-40
Lys972 and Arg63
POPC SAPC
How to Adapt
PC d/Å dev TM5/° dev TM9/° dev TM6/° dev
di(C14:0) 27 4.3 41.8 0.9 31.4 1.2 41.4 0.9
C14:0,C16:1 27 5.4 36.1 0.8 33.6 1.7 43.6 1.1
C16:0,C18:1 29 5.2 37.6 0.8 28.6 1.2 40.2 1.0
di(C18:1) 29 5.1 36.5 1.0 22.3 1.2 35.9 1.0
C18:0,C20:1 33 5.2 35.1 1.2 28.0 1.1 36.6 1.0
Within 8 Å
α
Thapsigargin Pocket
TM3TM5
TM7
Future Plans
Model lipid-protein setup with detergent
Develop “shape” model to describe ms dynamics of ATPase – lipid system
Acknowledging…Birgit SchiøttBiomodelling GroupDepartment of Chemistry
Maria MusgaardBiomodelling Group Department of Chemistry
Carsten WiufBiRCBioinformatics Research Center
Christian StormBiRC
Bioinformatics Research Center
Yonathan SonntagPoul Nissen groupDepartment of Molecular Biology Poul Nissen
Department of Molecular Biology
Anne-Marie Lund WintherPoul Nissen group
Department of Molecular Biology
Claus OlesenJesper Møller groupInstitute of Physiology and Biophysics
Jesper Vuust MøllerInstitute of Physiology and Biophysics
Activity Depend on Bilayer
DOPC
A.G. Lee, Biochimica et Biophysica Acta 1376 (1998) 381-390
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