Transcript Coarse-grain modeling of lipid membranes Mario Orsi University of Southampton

Coarse-grain modeling of
lipid membranes
Mario Orsi
University of Southampton
LAMMPS workshop, Albuquerque, 9 August 2011
http://en.wikibooks.org/wiki/Structural_Biochemistry/Lipids/Lipid_Bilayer
Membrane modeling
Water
Lipid
bilayer
Water
• Atomistic models:
– Accurate but computationally demanding
• Coarse-Grain (CG) models:
– Orders of magnitude faster to simulate
CG models of lipids and water
Klein et al., J Phys Chem B (2001); Smit et al., J Phys Chem B (2003);
Marrink et al., J Phys Chem B (2004, 2007); Izvekov and Voth, J Phys Chem B (2005);
Atomistic
Headgroup:
dipole moment ~ 20 D
Ester/glycerol:
dipole moments ~ 2 D
H2O:
dipole moment ~ 3 D
CG
•
CG Issues:
– Incomplete
electrostatics
– Water: generic
apolar fluid
– Lennard-Jones
combination rules
not followed:
εAB ≠(εAεB)1/2
Our CG model
[Orsi et al, J Phys Chem B, 2008]
•
•
•
Explicit electrostatics, relative dielectric constant r=1
– Lipid: charges for headgroup and dipoles for glycerol/ester
– Water: 1-site “SSD” dipolar model [Liu & Ichiye, J Phys Chem, 1996]
Tails: anisotropic “liquid-crystal” potential [Gay and Berne, J Chem Phys, 1981]
Bespoke MD code developed in-house
Membrane properties
J Phys: Condens Matter, 22, 155106 (2010)
CG/atomistic multiscale simulation
•
•
•
Fine chemical detail for
selected molecules
“Dual-resolution” system of
mixed granularities
Our CG model compatible
with atomistic potentials
[Michel et al, J Phys Chem B, 2008;
Orsi et al, J Phys Chem B, 2009]
•
Electrostatics: classical
Coulomb formulae
“Dual-resolution” systems
Drugs & hormones
[Soft Matter, 6, 3797 (2010)]
Antimicrobial compounds
[J R Soc Interface, 8, 826 (2011)]
Limitations of our methodology
Force field
• Gay-Berne potential
(ellipsoidal tails)
– Unrealistic
interdigitation when
simulating solid (“gel”)
bilayer phases
Software
• Our bespoke code
– Not parallel
– Not very flexible
• Using LAMMPS
instead?
Not straightforward:
– No SSD water
– Straight cutoff for
dipoles is problematic
New “ELBA” force field
ELectrostatics-BAsed coarse-graining
• Simplified water:
LJ + dipole
• Lipid tails: LJ
• Validated with inhouse program
• For challenging
applications, the
power of LAMMPS
is needed!
• LAMMPS “dipole/cut” pair
style
Potential
– Straight cutoff: discontinuities
in potential and force
– Poor energy conservation
– Artefacts in the particles’
motion
Energy
cut
sf
Derivative (force)
Force
• New shifted-force style
(“dipole/sf”)
– Modified formulae: potential &
force go to zero at the cutoff
[Allen & Tildesley, 1987]:
Derivative
(force) x10
Force zoomed
zoomed x10
LAMMPS NVE simulation of point dipoles
E
Shifted-force: better energy conservation + larger timesteps
ELBA in LAMMPS: preliminary MD results
Membrane
self-assembly
• Lipid/water
dispersion
• Lipid heads: red
• Lipid tails:
transparent
yellow
• Water: blue
ELBA in LAMMPS: membrane self-assembly
• 2 ns
• Phase
separation
ELBA in LAMMPS: membrane self-assembly
• 10 ns
• Water channel
forms
ELBA in LAMMPS: membrane self-assembly
• 30 ns
• Water channel
persists
ELBA in LAMMPS: membrane self-assembly
• 40 ns
• Water channel
thinning
ELBA in LAMMPS: membrane self-assembly
• 50 ns
• Water channel
disappears
• Remaining
defect: “thread”
of lipid
headgroups
ELBA in LAMMPS: membrane self-assembly
• 60 ns
• Defect-free,
stable bilayer
ELBA+LAMMPS perspectives
• More lipid
species
– Cholesterol
• Lipid mixtures
– Microdomain
(“raft”)
formation
• Dual-resolution
[From “The inner life of the cell”]
– Atomistic
proteins in CG
membrane
environment
Acknowledgements
• Jonathan Essex
• Julien Michel
(University of Edinburgh)
• Wendy Sanderson
• Massimo Noro
• Funding:
– UK taxpayers
– J&J
– Unilever