Transcript MD simulering

Peptide Aggregation and Pore
Formation in a Lipid Bilayer;
a Combined CG and AA MD Study
Lea Thøgersen, University of Aarhus
Pushing the Boundaries of Biomolecular Simulation
June 11, 2008
Outline



Introduction
Results
Conclusions

Coarse-Grained Molecular Dynamics

Alamethicin

Modelling Setup

NAMD CG vs MARTINI CG

Microsecond Action

Structure

Reverse Coarse-Graining

Water Pore Formation

Structural Changes
Coarse Grained MD – Why?
Coarse-graining
All-atom MD:
time step of 1-2 fs,
time frame sampled ~ 100 ns
• Reduction in degrees of freedom
• Fast frequenzy movements removed
• Smoother potential surface
• Longer time steps can be taken
• Microsecond simulations possible
Coarse-grained MD:
time step of 20-50 fs,
time frame sampled ~ 1 μs
Coarse Grained Molecular Dynamics
Shelley, Shelley, Reeder, Bandyopadhyay, Klein;
A Coarse Grain Model for Phospholipid Simulations
J. Phys. Chem. B (2001) 105 4464
Marrink, de Vries, Mark;
Coarse Grained Model for
Semiquantitative Lipid Simulations
J. Phys. Chem. B (2004) 108 750
Shih, Arkhipov, Freddolino, Schulten;
Coarse Grained Protein-Lipid Model
with Application to Lipoprotein Particles
J. Phys. Chem. B (2006) 110 3674
NAMD CG
MARTINI CG
Marrink, Risselada, Yefimov, Tieleman, de Vries;
Monticelli, Kandasamy, Periole, Larson, Tieleman, Marrink;
The MARTINI Force Field: Coarse Grained Model
for Biomolecular Simulations
The MARTINI Coarse-Grained Force Field:
Extension to Proteins
J. Phys. Chem. B (2007) 111 7812
J. Chem. Theory and Comput. (2008) 4 819
Alamethicin

20 amino acid antimicrobiel peptide.

Part of the immune system (for fungi).

Forms channels in membranes which allow
water and ions to go through.

Destroys membrane potential.
Gln19
Glu18
Motivation:
Potentially a good and simple
membrane channel model
Insight into this family of proteins could
be valuable in the development of
antibiotics
Gln7
Widely Accepted Channel Model
Tieleman, Hess, Sansom;
Analysis and Evaluation of Channel Models:
Simulations of Alamethicin.
Biophys. J. (2002) 83 2392
Spaar, Münster, Salditt;
Conformation of Peptides in Lipid Membranes
Studied by X-Ray Grazing Incidence Scattering.
Biophys. J. (2004) 87 396
Modelling Setup
To study alamethicin interaction
with membrane and each other
25 peptides
330 DMPC lipids
26452 water
~117000 atoms
~ 11700 beads
PBC 120 Å × 124 Å × 90 Å
NAMD CG versus MARTINI CG
4
GLY
ALA
4
AIB
Apolar
1
2
degree of polarity 1-5
1
Polar
2
4
Nda
degree of polarity 1-5
C
C
NAMD
MARTINI
C
(MARTINI)
Nda
NAMD CG
Nda
AA
N0
2
MARTINI CG
Nonpolar
donor
hydrogenbond
acceptor
both
C5
none
C4
(NAMD)
Charged
1
donor
hydrogenbond
acceptor
both
none
Alamethicin Behavior
Alamethicin
C-term
Hydrophilic
sidechains
Lipid
Polar
headgroup
Non-polar
tails
N-term
7 ns
120 ns
32 ns
Peptide Aggregation I
0-1 μs
Peptide Aggregation II
MARTINI
NAMD
0 μs
1 μs
4 μs
Structure of the Clusters
0
0.5
Gln7
1
Gln7
Helix Tilt
Alamethicin, DMPC lipid
peptid:lipid - 1:15
15N-Aib8 alamethicin
θ
Aib8
Exp
θ = 10˚
0.04
MD
0.03
0.02
0.01
0
0
30
60
90
Helix tilt / deg.
120
Vosegaard, Bertelsen, Pedersen, Thøgersen,
Schiøtt, Tajkhorshid, Skrydstrup, Nielsen;
Resolution Enhancement in Solid-State NMR
of Oriented Membrane Proteins
by Anisotropic Differential Linebroadening
JACS (2008) 130 5028
Reverse Coarse-Graining
AA
t = 0μs
CG
t = 0μs
CG
t = 1μs
AA - rev CG
t = 1μs
AA
after SA
CG water
vs
AA water
δ-
Class: Polar
δ+
δ+
5.0Å
900-1000 ns
TIP3P model
2.8Å
35-40 ns
Structural Changes
18 of 25 peptides remain α-helical
Conclusions

Alamethicin monomers readily aggregate and
form clusters that grow in size over time.

Large diversity in form of clusters and structure
of peptides.

Reverse CG required to

obtain detailed water interaction

validate results obtained on the long time scale
Acknowledgements
Emad Tajkhorshid & the NAMD people
Theoretical and Computational Biophysics Group
University of Illinois at Urbana-Champaign, USA
Birgit Schiøtt
& the Biomodelling Group
Department of Chemistry
University of Aarhus, Denmark
Niels Christian Nielsen & Thomas Vosegaard
Laboratory for Biomolecular NMR spectroscopy
Department of Chemistry
University of Aarhus, Denmark
Funding:
&