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

[Thomas Piggot]

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.uk/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.