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 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