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Modelling of Protein-Lipid Interactions

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

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Modelling of Protein-Lipid Interactions

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  1. Modelling of Protein-Lipid Interactions Lea Thøgersen PUMPKIN Opfølgningsmøde February 24, 2009

  2. Outline • A PUMPKIN Postdoc • Work in Progress • Future Work

  3. 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

  4. Membrane Proteins

  5. 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

  6. 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

  7. All-Atom MD Study • E2 form (Thapsigargin-like inhibitor removed from the structure). • No Ca2+ ions, 0.2M K++Cl- O O +2 SAPC DOPC DOPC O O O POPC O O O O DMPC -2 MPPC O

  8. MD X-ray X-ray lipids in orange POPC – TRP shown

  9. SERCA Position in Bilayer DMPC MPPC POPC DOPC SAPC A.G. Lee, Biochimica et Biophysica Acta 1612 (2003) 1-40

  10. Lys972 and Arg63 POPC SAPC

  11. How to Adapt α Within 8 Å

  12. Thapsigargin Pocket TM5 TM3 TM7

  13. Future Plans • Model lipid-protein setup with detergent • Develop “shape” model to describe ms dynamics of ATPase – lipid system

  14. Acknowledging… Maria Musgaard Biomodelling Group Department of Chemistry Birgit Schiøtt Biomodelling Group Department of Chemistry Anne-Marie Lund Winther Poul Nissen group Department of Molecular Biology Yonathan Sonntag Poul Nissen group Department of Molecular Biology Poul Nissen Department of Molecular Biology Claus Olesen Jesper Møller group Institute of Physiology and Biophysics Jesper Vuust Møller Institute of Physiology and Biophysics Carsten Wiuf BiRC Bioinformatics Research Center Christian Storm BiRC Bioinformatics Research Center

  15. Activity Depend on Bilayer DOPC A.G. Lee, Biochimica et Biophysica Acta 1376 (1998) 381-390

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