[gmx-users] How to use Höltje's cholesterol parameters ?

Tue Dec 20 17:18:16 CET 2016

Hello,

Thank you very much for your reply.

You are probably right. This is quite frustrating to observe that everyone
sometimes seems to use its own recipe for MD simulations of bilayers
without giving enough details to allow others to compare or exactly
reproduce their results. In this regard, I must say that your paper
comparing several forcefields for their ability to reproduce
phosphatidylcholine bilayers was a remarkably useful contribution imo.
I could indeed test these things by myself and, in a way, I started to do
so since I've launched 200 ns equilibrations of bilayers built with
solution 1 and 2. Unfortunately, it becomes complicated because I don't
have experimental data on which I can rely to select the best solution.
Moreover, I slightly modified the topology to get sitosterol instead of
cholesterol (just a minor methyl change from cholesterol) to get a
biologically relevant system for my work, making even less likely to find
experimental data for this. Both solutions result in a consistent ordering
effect when compared with pure phosphatidylcholine bilayers, but this
ordering effect is slightly different when comparing the solutions with
each other. Solution 1 also seems to lead to a slightly higher area per
lipid than solution 2, but here again, which one is closer from the "truth"
?
I will for sure have a look at the discussion you mention.

I am indeed simulating PC phosopholipids, so I think it shoudl be OK to use
Berger Lipids to this purpose.

I think I will at least try to simulate something with the 54A7 parameters
of Poger et al. since it does not require a lot of work from where I am at
this point and since it would already make a comparison possible.

About CHARMM36 (or other forcefield), I will for sure give it a try for my
next project, but I am not sure if it will be worth doing here as I have
already lost some time in refining simulation parameters and given the poor
results that I got so far...

Thank you again for your nice reply.

2016-12-20 15:44 GMT+01:00 Thomas Piggot <t.piggot at soton.ac.uk>:

> Hi,
>
> Not sure how much I can help here as I've not used these Holtje parameters
> or indeed even simulated cholesterol all that much before but hopefully I
> say a couple of general things that might be of use.
>
> Firstly, this is a good question and I think that lack of responses is
> probably due to the fact the no-one has really tested these different types
> of combinations. If someone knows otherwise, please feel free to correct
> me. You could obviously test these things yourself, but that would require
> a fair amount of work. What I do know about the Berger/Holtje combination
> is that it is thought to result in a too much of an ordering (see, for
> example, some of the discussions at http://nmrlipids.blogspot.co.u
> k/2016/07/nmrlipids-iii-preliminary-observations.html). I'm unsure if
> this is with the standard cholesterol tail atomtypes or with Berger types,
> as you suggest you might want to use.
>
> A second point is related to the Berger force field in general. Unless you
> are simulating PC phospholipids, you should avoid using this force field.
> There are several papers that show that things don't work well for
> different non-PC based lipids.
>
> Finally, and you sort of touched upon this, to avoid these issues you
> could just use a different force field. You mention that you already have
> GROMOS topologies for your small molecules and that there are cholesterol
> parameters available from the ATB; there are also compatible phospholipid
> parameters too. For PC lipids you have the choice of the 53A6L/54A7
> parameters of Poger et al. (included in the 54A7 rtp and also available
> from the ATB), or the Kukol/GROMOS-CKP parameters (these ones are available
> to download from Lipidbook or I can send stuff off list). For these latter
> parameters, there are also lots of different lipids types available which
> work pretty well in general (like any force field, I definitely wouldn't
> claim that they are perfect though). You could also switch to a completely
> different force field all together and use, for example, one of the
> all-atom CHARMM36, Slipids or LIPID14 force fields. These will likely have
> the lipid parameters you need but you would need to parameterise the small
> molecules. The latter two are AMBER based and so you could use GAFF for
> this, for CHARMM36 you can use CGenFF. Frankly, I'd suggest doing the
> simulations using a couple of different force fields anyway to try and be
> sure of anything you see, if you have the time/compute to do so.
>
> Hopefully that is some sort of help, sorry I can't give more specific
> advice directly on your questions.
>
> Cheers
>
> Tom
>
>
> On 20/12/16 14:09, Sim gmx wrote:
>
>> Anyone ?
>> Do you think it does not deserve any attention given the similiraties
>> between GROMOS87 and GROMOS96 FF ?
>>
>> 2016-12-12 9:38 GMT+01:00 Sim gmx <simgmx at gmail.com>:
>>
>> Please, could someone help me with that ? Are my questions unclear ?
>>>
>>> 2016-12-09 9:48 GMT+01:00 Sim gmx <simgmx at gmail.com>:
>>>
>>> Hello everyone,
>>>>
>>>> I am currently working on interactions between small biomolecules and
>>>> bilayers. Phospholipids parameters come from Peter Tieleman's website
>>>> (Berger lipids forcefield) and the small compounds are parametrized for
>>>> gromos53a6. I would like to add cholesterol to my bilayers, which is
>>>> very
>>>> frequently done with Höltje cholesterol parameters (see e.g.
>>>> http://pubs.acs.org/doi/full/10.1021/ja211929h ). However, these Höltje
>>>> parameters were originally designed for the ffgmx forcefield, which is
>>>> quite old.
>>>>
>>>> The way we should include these parameters in a Berger lipids -
>>>> gromos53a6 mixed forcefield has already raised some questions on the
>>>> mailing list: http://comments.gmane.org/gman
>>>> e.science.biology.gromacs.user/68478
>>>>
>>>> However, it remains unclear to me. I guess we can use the bonded
>>>> parameters as they are written in the original topology from Höltje,
>>>> but it
>>>> becomes more complicated when talking about the non bonded interactions.
>>>> Every atomtypes but two (CB and CR61) from ffgmx also exist in
>>>> gromos53a6
>>>> (and are thus included in the gromos53a6 forcefield). Hence, I think
>>>> there
>>>> are 3 possible ways to make a simulation run without crashing when
>>>> including this cholesterol to a berger lipid - gromos53a6 forcefield:
>>>>
>>>> 1) Keeping the cholesterol topology file unchanged, and adding the
>>>> atomtypes 'CB' and 'CR61' to the forcefield file 'ffnonbonded.itp', with
>>>> their parameters coming from the ffgmx forcefield. It means that each
>>>> cholesterol will be seen as a "hybrid object", with most of the
>>>> atomtypes
>>>> being gromos53a6 ones, and CB and CR61 being ffgmx atomtypes. Non bonded
>>>> interaction involving CB or CR61 atomtypes will be computed with the
>>>> standard combination rule.
>>>>
>>>> 2) Keeping the Berger lipid - gromos53a6 forcefield unchanged, and
>>>> changing the atomtype 'CB' to 'C' and the atomtype 'CR61' to 'CR1' into
>>>> the
>>>> cholesterol topology file, C and CR1 being the corresponding atomtypes
>>>> found in gromos53a6. It means that each cholesterol will be seen as a
>>>> "gromos53a6" object for the non bonded interactions.
>>>>
>>>> 3) Changing every atomtype from the cholesterol topology file to make
>>>> them different from gromos53a6 atomtypes (for instance: CH2 becomes CH2F
>>>> (for ffgmx)) and adding all these ffgmx specific atomtypes in the
>>>> forcefield file 'ffnonbonded.itp' with the proper parameters. It means
>>>> that
>>>> each cholesterol will be seen as a "ffgmx object", each non bonded
>>>> interaction being computed with the standard combination rule.
>>>>
>>>> Solution 1 seems to be quite obvious, but it sounds a bit weird to me,
>>>> because it mixes up ffgmx and 53a6 interactions. Solution 2 seems more
>>>> consistent, but if we use "pure" gromos53a6 non bonded interactions,
>>>> maybe
>>>> we should also "translate" bonded parameters from ffgmx to gromos53a6 ?
>>>> Solution 3 is maybe the most logical solution, but it seems that ffgmx
>>>> is
>>>> now considered to be deprecated...
>>>>
>>>> The question becomes even more complicated when considering the fact
>>>> that
>>>> CH2 and CH3 atomtypes could lead to overcondensed bilayers, according to
>>>> some authors who advise to switch them to 'LP2' and 'LP3' Berger lipid
>>>> atomtypes.
>>>>
>>>> It is possible that those solutions give quite similar results (if ffgmx
>>>> and gromos53a6 forcefields are "similar enough"), but I am very curious
>>>> to
>>>> know the 'usual' protocol that is followed when people only write
>>>> "Höltje
>>>> parameters were used".
>>>>
>>>> Another solution would be to use the cholesterol topology file found on
>>>> ATB (manual validation), frequently used by Pr. Alan E. Mark, but never
>>>> used with Berger lipids phospholipids...
>>>>
>>>> Thank you in advance for your help!
>>>>
>>>>
>>>
> --
> Dr Thomas Piggot
> Visiting Fellow
> University of Southampton, UK.
>
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