Simulating lipid bilayers

with CHARMM
CECAM workshop Dublin/DC

The question that haunts every one of us

How do you know what youve

simulated is not complete junk?

Older people (some may even be in this room) have

strong opinions on this.
We ignore their advice at our own risk.
What follows is my interpretation.

Lipid bilayers
water

head groups,
often zwitterionic

glycerol groups

alkyl tails in the

hydrophobic core

C36, 1 s
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Original C22 lipid forcefield

parameterization based on
small molecules

QM data, exp. thermo

n-tetradecane, 25 C (liquid)

C27
AMBER99
C27r
QM

C27r

AMBER99
Klauda, Brooks, MacKerell, Jr., Venable & Pastor, J. Phys. Chem. B. 2005

alexsodt@gmail.com

better QM leads to gauche-trans

barrier lowered, gauche basin
widened...

long constant area simulations

xz

yz

C27r, 1 s

C27r (1 s)
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C27 (0.2 s)

Simulations by Senthil Kandasamy of the DE Shaw lab

like a gel

Why is it so hard to get the surface area right?

Bilayer surface tension
a small difference in
large numbers,
reflecting delicate
balance of stresses
head group attraction balances chain repulsion
+"

$ = ! ( p N # pT ( z ))dz = 0
#"

alexsodt@gmail.com

C36

Alex MacKerell: recalculated glycerol/ester charges

Jeff Klauda: high level QM on glycerol/ester torsions;
lots of bilayer and monolayer sims
Rick Venable: fit torsional populations against
experiment to identify problem torsions; many sims
Doug Tobias: analysis of low hydration DOPC
D.E. Shaw group: independent test on superfast
computer

Klauda/Venable/Feites/OConnor/Tobias/Mondragon-Ramirez/Vorobyov/Mackerell/Pastor
JPC B 2010, 114/7830

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NMR measured order parameters

NPAT
A=64

no splitting at G1 and C2

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NMR order parameter

example
/home/alex/order_parameter_example

Chain order parameters for trajectory

(C13)
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Area per lipid of DPPC = 63.0 2

Adjusting carbonyl changes and running at NPT:

NPT:

alexsodt@gmail.com

Area per lipid of DPPC = 63.0 2

Adjusting carbonyl changes and running at NPT:

NPT:

k T Atot
( d" %
Ka = A & # = B
' dA $T
!Atot 2

Area compressibility modulus

ca. 236 +/- 31 (dyn/cm)
Exp: 234 +/- 23
C27r: 140 +/- 25
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C27r, 1 s

C27r (1 s)
alexsodt@gmail.com

C27, 200 ns

C22r (0.2 s)

C36, 1 s

C36 (1 s)

Surface areas, compressibilities very good at NPT

lipid
DPPC
DMPC
DLPC
DOPC (lo)
DOPC (hi)
POPC
POPE

Area/lipid (2)
sim
expt
62.9 0.3
63.0 1.0
60.8 0.2
60.6 0.5
64.4 0.3
63.2 0.5
60.1 0.1
59.3 0.7
69.0 0.3
67.4 to 72 ??
64.7 0.2
68.3 1.5 ??
59.2 0.3
59.8-60.8

DPPC
DMPC
DOPC

KA (dyn/cm)
236 31
234 23
250
265 18
Klauda et al, JPCB, 2010

Coarse-grained model to estimate size

dependence
Some effect on order reorientational relaxation:
ca. 1-2% for |SCD|
alexsodt@gmail.com

New Lipids?
Cardiolipin

Expected to have high curvature

charge (-1) at low pH, (-2) at pH 7 (reconfirmed
by Kevin Song and Klaus Gawrisch)

Study motivated by simulations by Dahlberg/

Maliniak using Berger FF/GROMOS

System

T (K)

TMCL

72

328

50 ns

TOCL

72

310

50 ns

DOPC

72

310

50 ns

DMPC

72

328

50 ns

Berger
TOCL

64

310

300 ns

alexsodt@gmail.com

duration A/chain
28.3
(0.05)
31.8
(0.09)
34.7
(0.9)
31.6
(0.9)

24.8

KA (dyn/
cm)
321(25)
282(26)

250
239

1100

Structure?
0.250
0.200

SCD

0.150

sim (orig)

0.100

expt

0.050
0.000
2

10

12

14

16

Carbon Number

Order high/Area low

NBfix
! AB =

! A +! B
2

+ ! fix

Benoit Roux (and co-workers) used

this approach to correct
overbinding of Na+ to peptide C=O

NBfixd
0.250
0.200

SCD

0.150

sim (orig)
sim (NBFIX)
expt

0.100
0.050
0.000
2

10

12

Carbon Number

14

16

Some points

Surface area/tension is sensitive to parameterization (like cutoffs). Dont freestyle it! CHARMM-GUI it, check the papers that
test bilayer properties, or ask someone that knows
(documentation will give too many options).

Water model an obvious weak point, but all parameters are based
on TIP3P and would change if a better model were used.

For your important observable it may be a good idea to check at

different tensions/areas to make sure the observable is insensitive
to the tension/area.

Pastor and Mackerell Jr., JPC lett. 2011 v2 1526

P21/Images

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P1 Periodic Boundary Conditions

Neighboring cells are integer lattice vectors

P21 Periodic Boundary Conditions

Green: Top
Leaflet
Blue: Bottom
Leaflet
(green and blue are
symmetry equivalent)

Cell (plus symmetry atoms) is twice as big

Symmetry related atoms: (-x,y+1/2,-z)
Tilted square: original cell (without symmetry atom)

P21

alexsodt@gmail.com

Why is it so hard to get the surface area right?

Bilayer surface tension
a small difference in
large numbers,
reflecting delicate
balance of stresses
head group attraction balances chain repulsion
+"

$ = ! ( p N # pT ( z ))dz = 0
#"

alexsodt@gmail.com

P21 Example
/home/alex/p21_example

alexsodt@gmail.com

text files
of restrained
peptide
position

http://membrane.urmc.rochester.edu/content/wham
alexsodt@gmail.com

Bilayer free energy

example
/home/alex/free_energy_example

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Bilayer timescales
Isomerization
Triangles, lipid
chains
circles,
hexadecane
Venable, Zhang, Hardy, Pastor
alexsodt@gmail.com

Bilayer timescales
Lipid diffusion
DPPC
9.5x10-8 cm2/s
0.95 2/ns

Klauda/Brooks/Pastor J. Chem. Phys. 125 144710 2006

10x10-8 cm2/ns =1 2/ns

Kim/Lee/Morris/Pastor/Andersen/Im
Biophysical J. v102 1551

Peptide/Bilayer timescales?
Minor comment in next part, but for
a transmembrane helix dimer,
reorientation of helices may take
longer than a microsecond.

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