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Ceramides
- Jingjie Yeo
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9 years 5 months ago #4183
by Jingjie Yeo
Ceramides was created by Jingjie Yeo
I am trying to simulate a pure ceramdie lipid bilayer using the parameters from:
; C.A. Lopez, Z. Sovova, F.J. van Eerden, A.H. de Vries, S.J. Marrink.
; Martini force field parameters for glycolipids.
; J. Chem. Theory Comput., 9, 1694-1708, 2013.
However, when I try to equilibrate a 512 ceramide bilayer, after 200ns the system becomes unstable and the bilayer structure cannot be maintained. Extremely large rippling occurs and the bilayer starts to collapse. May I know whether this is a problem with my input? I have used the martini_v2.0_lipids.itp and the martini_v2.1_CNP.itp.
; C.A. Lopez, Z. Sovova, F.J. van Eerden, A.H. de Vries, S.J. Marrink.
; Martini force field parameters for glycolipids.
; J. Chem. Theory Comput., 9, 1694-1708, 2013.
However, when I try to equilibrate a 512 ceramide bilayer, after 200ns the system becomes unstable and the bilayer structure cannot be maintained. Extremely large rippling occurs and the bilayer starts to collapse. May I know whether this is a problem with my input? I have used the martini_v2.0_lipids.itp and the martini_v2.1_CNP.itp.
;
; STANDARD MD INPUT OPTIONS FOR MARTINI 2.x
; Updated 02 feb 2013 by DdJ
;
; for use with GROMACS 4.5/4.6
;
title = Martini
; TIMESTEP IN MARTINI
; Most simulations are numerically stable
; with dt=40 fs, some (especially rings and polarizable water) require 20-30 fs.
; Note that time steps of 40 fs and larger may create local heating or
; cooling in your system. Although the use of a heat bath will globally
; remove this effect, it is advised to check consistency of
; your results for somewhat smaller time steps in the range 20-30 fs.
; Time steps exceeding 40 fs should not be used; time steps smaller
; than 20 fs are also not required unless specifically stated in the itp file.
integrator = md
dt = 0.02
nsteps = 10000000 ; 20 * 10,000,000 = 200 ns
nstcomm = 100
comm-grps = CER W
; OUTPUT CONTROL OPTIONS =
; Output frequency for coords (x), velocities (v) and forces (f) =
nstxout = 1000
nstvout = 1000
nstlog = 1000 ; Output frequency for energies to log file
nstenergy = 1000 ; Output frequency for energies to energy file
;nstfout = 2500
;nstxtcout = 2500 ; Output frequency for .xtc file
;xtc_precision = 100
;xtc-grps =
;energygrps = CER W
; NEIGHBOURLIST and MARTINI
; Due to the use of shifted potentials, the noise generated
; from particles leaving/entering the neighbour list is not so large,
; even when large time steps are being used. In practice, once every
; ten steps works fine with a neighborlist cutoff that is equal to the
; non-bonded cutoff (1.2 nm). However, to improve energy conservation
; or to avoid local heating/cooling, you may increase the update frequency
; and/or enlarge the neighbourlist cut-off (to 1.4 nm). The latter option
; is computationally less expensive and leads to improved energy conservation
nstlist = 10
ns_type = grid
pbc = xyz
rlist = 1.4
; MARTINI and NONBONDED
; Standard cut-off schemes are used for the non-bonded interactions
; in the Martini model: LJ interactions are shifted to zero in the
; range 0.9-1.2 nm, and electrostatic interactions in the range 0.0-1.2 nm.
; The treatment of the non-bonded cut-offs is considered to be part of
; the force field parameterization, so we recommend not to touch these
; values as they will alter the overall balance of the force field.
; In principle you can include long range electrostatics through the use
; of PME, which could be more realistic in certain applications
; Please realize that electrostatic interactions in the Martini model are
; not considered to be very accurate to begin with, especially as the
; screening in the system is set to be uniform across the system with
; a screening constant of 15. When using PME, please make sure your
; system properties are still reasonable.
;
; With the polarizable water model, the relative electrostatic screening
; (epsilon_r) should have a value of 2.5, representative of a low-dielectric
; apolar solvent. The polarizable water itself will perform the explicit screening
; in aqueous environment. In this case, the use of PME is more realistic.
;
; For use in combination with the Verlet-pairlist algorithm implemented
; in Gromacs 4.6 a straight cutoff in combination with the potential
; modifiers can be used. Although this will change the potential shape,
; preliminary results indicate that forcefield properties do not change a lot
; when the LJ cutoff is reduced to 1.1 nm. Be sure to test the effects for
; your particular system. The advantage is a gain of speed of 50-100%.
coulombtype = Shift ;Reaction_field (for use with Verlet-pairlist) ;PME (especially with polarizable water)
rcoulomb_switch = 0.0
rcoulomb = 1.2
epsilon_r = 15 ; 2.5 (with polarizable water)
vdw_type = Shift ;cutoff (for use with Verlet-pairlist)
rvdw_switch = 0.9
rvdw = 1.2 ;1.1 (for use with Verlet-pairlist)
;cutoff-scheme = verlet
;coulomb-modifier = Potential-shift
;vdw-modifier = Potential-shift
;epsilon_rf = 0 ; epsilon_rf = 0 really means epsilon_rf = infinity
;verlet-buffer-drift = 0.005
; MARTINI and TEMPERATURE/PRESSURE
; normal temperature and pressure coupling schemes can be used.
; It is recommended to couple individual groups in your system separately.
; Good temperature control can be achieved with the velocity rescale (V-rescale)
; thermostat using a coupling constant of the order of 1 ps. Even better
; temperature control can be achieved by reducing the temperature coupling
; constant to 0.1 ps, although with such tight coupling (approaching
; the time step) one can no longer speak of a weak-coupling scheme.
; We therefore recommend a coupling time constant of at least 0.5 ps.
; The Berendsen thermostat is less suited since it does not give
; a well described thermodynamic ensemble.
;
; Pressure can be controlled with the Parrinello-Rahman barostat,
; with a coupling constant in the range 4-8 ps and typical compressibility
; in the order of 10-4 - 10-5 bar-1. Note that, for equilibration purposes,
; the Berendsen barostat probably gives better results, as the Parrinello-
; Rahman is prone to oscillating behaviour. For bilayer systems the pressure
; coupling should be done semiisotropic.
tcoupl = v-rescale
tc-grps = CER W
tau_t = 1.0 1.0
ref_t = 310 310
Pcoupl = berendsen ; parrinello-rahman
Pcoupltype = semiisotropic ; semiisotropic
tau_p = 3.0 ; 12.0 12.0
;parrinello-rahman is more stable
;with larger tau-p, DdJ, 20130422
compressibility = 3e-4 3e-4 ; 3e-4
ref_p = 1.0 1.0 ; 1.0 1.0
refcoord_scaling = all
gen_vel = yes
gen_temp = 310
gen_seed = 473529
; MARTINI and CONSTRAINTS
; for ring systems and stiff bonds constraints are defined
; which are best handled using Lincs.
constraints = none
constraint_algorithm = Lincs
continuation = no
lincs_order = 4
lincs_warnangle = 30Please Log in or Create an account to join the conversation.
- mnmelo
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9 years 5 months ago - 9 years 5 months ago #4186
by mnmelo
Replied by mnmelo on topic Ceramides
Hi Jingjie, welcome to the Forum,
If by 'ceramide' you mean pure ceramide, without any headgroup, then what you are trying to do won't work. Pure ceramide does not form bilayers.
Sphingolipids or glyco-ceramides, which have larger, more polar heads, should be bilayer-forming. However, I am not sure that all of the lipids in the paper you mentioned have been tested on pure bilayers on their own, even experimentally.
Cheers,
Manel
If by 'ceramide' you mean pure ceramide, without any headgroup, then what you are trying to do won't work. Pure ceramide does not form bilayers.
Sphingolipids or glyco-ceramides, which have larger, more polar heads, should be bilayer-forming. However, I am not sure that all of the lipids in the paper you mentioned have been tested on pure bilayers on their own, even experimentally.
Cheers,
Manel
Last edit: 9 years 5 months ago by mnmelo.
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9 years 5 months ago #4187
by Jingjie Yeo
Replied by Jingjie Yeo on topic Ceramides
Kindly correct me if I'm wrong, but aren't ceramides in the skin bilayer-forming? Maybe I have misunderstood the structure that was modelled in the paper, but is it not a sphingosine moiety esterified to a fatty acid, in which case it should be representative of the ceramides found in skin?
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9 years 5 months ago #4188
by helgi
Replied by helgi on topic Ceramides
Hello, hello,
Let me chime in here. Indeed there are a lot of ceramide-based lipids in the skin but all kinds (different heads and tails). These are also mostly in the dead cell / lipid matrix part which I doughty form regular bilayers, but this is not something I know much about so please read up on that. For the “regular” ceramide, a sphingosine linked to another fatty acid, if the other tail is typical (e.g. C18, C18:1, etc tail) that lipid will have two rather regular tails but only a OH group as a head so on average resembling an inverted cone and therefore really wants to adopt an inverted micelle shape e.g. not a good bilayer former.
Hope this helps,
Cheers,
- Helgi
Let me chime in here. Indeed there are a lot of ceramide-based lipids in the skin but all kinds (different heads and tails). These are also mostly in the dead cell / lipid matrix part which I doughty form regular bilayers, but this is not something I know much about so please read up on that. For the “regular” ceramide, a sphingosine linked to another fatty acid, if the other tail is typical (e.g. C18, C18:1, etc tail) that lipid will have two rather regular tails but only a OH group as a head so on average resembling an inverted cone and therefore really wants to adopt an inverted micelle shape e.g. not a good bilayer former.
Hope this helps,
Cheers,
- Helgi
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9 years 5 months ago #4189
by mnmelo
Replied by mnmelo on topic Ceramides
Hi Jingjie,
I'm no expert on it, but after a brief search on the subject ( Coderch et al. Am J Clin Dermatol 4(2):107 ) I can already tell you that the skin ceramide bilayers you mention, present in the intercellular stratum corneum matrix, are very unlikely to remain stable individually in water. They are lamellar in vivo due, probably, to a number of factors:
- They start out as lamellar bodies enriched in phospholipids and glycosphingolypids. It is only after these lamellae stack that they mature (i.e. polar headgroups are digested) into mostly ceramide-containing structures (but also with cholesterol and free fatty acids).
- The mature lamellae, being stacked, have a very low hydration. They are also tethered to each other; i.e. some lipids span two bilayers. The structure is further supported by protein anchoring to the stratum corneum cells.
This whole structured stacking+maturation process is probably what drives ceramide into a stable set of bilayers. Maybe you can try reproducing that in your model. But I wouldn't expect starting off with a pure ceramide bilayer to work, just as it won't work experimentally if you take pure ceramide and put it in water.
Otherwise I guess Nature could have saved herself the trouble of all this maturation process and just have stratum corneum/granulosum cells throw ceramide into the matrix and let it spontaneously form bilayers.
Cheers,
Manel
I'm no expert on it, but after a brief search on the subject ( Coderch et al. Am J Clin Dermatol 4(2):107 ) I can already tell you that the skin ceramide bilayers you mention, present in the intercellular stratum corneum matrix, are very unlikely to remain stable individually in water. They are lamellar in vivo due, probably, to a number of factors:
- They start out as lamellar bodies enriched in phospholipids and glycosphingolypids. It is only after these lamellae stack that they mature (i.e. polar headgroups are digested) into mostly ceramide-containing structures (but also with cholesterol and free fatty acids).
- The mature lamellae, being stacked, have a very low hydration. They are also tethered to each other; i.e. some lipids span two bilayers. The structure is further supported by protein anchoring to the stratum corneum cells.
This whole structured stacking+maturation process is probably what drives ceramide into a stable set of bilayers. Maybe you can try reproducing that in your model. But I wouldn't expect starting off with a pure ceramide bilayer to work, just as it won't work experimentally if you take pure ceramide and put it in water.
Otherwise I guess Nature could have saved herself the trouble of all this maturation process and just have stratum corneum/granulosum cells throw ceramide into the matrix and let it spontaneously form bilayers.
Cheers,
Manel
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9 years 5 months ago - 9 years 5 months ago #4193
by Jingjie Yeo
Replied by Jingjie Yeo on topic Ceramides
Thanks guys for the wonderful comments.
Helgi:
As Manel had pointed out, they do indeed form bilayers, albeit in a stacked formation. Bouwstra et al has provided significant resources with regard to this, in case anyone is interested:
www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Bouwstra%20JA [au]&dispmax=50
On another note, lets say I would like to increase the tail length (eg. C24), is it a process of simply adding C1 beads?
Manel:
I would agree with you regarding the stacked bilayers, maybe I can reproduce that together with low hydration. However, in your opinion, would that invalidate the many MD studies that showed pure ceramide bilayers being stable in water, just to name a couple:
www.sciencedirect.com/science/article/pii/S0006349507714601
pubs.acs.org/doi/abs/10.1021/ct400431e
In fact, for my own fully atomistic MD studies, it does show that pure ceramide bilayers are stable in water. Would that be simply because of shorter timescales which does not allow the bilayer to destabilize?
Helgi:
As Manel had pointed out, they do indeed form bilayers, albeit in a stacked formation. Bouwstra et al has provided significant resources with regard to this, in case anyone is interested:
www.ncbi.nlm.nih.gov/pubmed?cmd=search&term=Bouwstra%20JA [au]&dispmax=50
On another note, lets say I would like to increase the tail length (eg. C24), is it a process of simply adding C1 beads?
Manel:
I would agree with you regarding the stacked bilayers, maybe I can reproduce that together with low hydration. However, in your opinion, would that invalidate the many MD studies that showed pure ceramide bilayers being stable in water, just to name a couple:
www.sciencedirect.com/science/article/pii/S0006349507714601
pubs.acs.org/doi/abs/10.1021/ct400431e
In fact, for my own fully atomistic MD studies, it does show that pure ceramide bilayers are stable in water. Would that be simply because of shorter timescales which does not allow the bilayer to destabilize?
Last edit: 9 years 5 months ago by Jingjie Yeo.
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