Modelling of protein lipid interactions
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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

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Modelling of Protein-Lipid Interactions

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Modelling of protein lipid interactions

Modelling of Protein-Lipid Interactions

Lea Thøgersen

PUMPKIN Opfølgningsmøde

February 24, 2009


Outline

Outline

  • A PUMPKIN Postdoc

  • Work in Progress

  • Future Work


A pumpkin postdoc

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

Membrane Proteins


Protein lipid interactions

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

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

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


Modelling of protein lipid interactions

MD

X-ray

X-ray lipids in orange

POPC – TRP shown


Serca position in bilayer

SERCA Position in Bilayer

DMPC MPPC POPC DOPC SAPC

A.G. Lee, Biochimica et Biophysica Acta 1612 (2003) 1-40


Lys972 and arg63

Lys972 and Arg63

POPC SAPC


How to adapt

How to Adapt

α

Within 8 Å


Thapsigargin pocket

Thapsigargin Pocket

TM5

TM3

TM7


Future plans

Future Plans

  • Model lipid-protein setup with detergent

  • Develop “shape” model to describe ms dynamics of ATPase – lipid system


Acknowledging

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


Activity depend on bilayer

Activity Depend on Bilayer

DOPC

A.G. Lee, Biochimica et Biophysica Acta 1376 (1998) 381-390


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