[gmx-users] Using ATB to generate valid topologies

Thu Jul 14 08:34:09 CEST 2016

Tks for the references. 

For the record, here are the references for ATB:
DOI: 10.1021/ct200196m <http://pubs.acs.org/doi/abs/10.1021/ct200196m>
DOI:10.1089/cmb.2012.0239 <http://dx.doi.org/10.1089/cmb.2012.0239>
DOI:10.1007/s10822-014-9713-7 <http://dx.doi.org/10.1007/s10822-014-9713-7>

X-

> On 13 Jul 2016, at 17:39, Justin Lemkul <jalemkul at vt.edu> wrote:
> 
> 
> 
> On 7/13/16 11:02 AM, XAvier Periole wrote:
>>>> 
>>>> Just for the record ATB is a very good tool to build a start up topology. They also have a large set of topologies available on the site.
>>>> 
>>>> The charges are determined by QM and the user chooses the level of accuracy.
>>>> The bonded and LJ parameters are chosen based on the type of atom and it connectivity. Most atom types are already existing.
>>>> 
>>>> The sad part of ATB and other automated topology builders is that it is difficult to make a correct topology without putting the hands in.
>>>> 
>>>> Note that the CHARMM topology builder is even worst that ATB, but it gives you consistent topologies with existing ones.
>>>> 
>>> 
>>> Which CHARMM topology builder?  CGenFF or ParamChem?  I'd be curious to know the basis upon which this claim is made.
>> My experience in building CHARMM topologies … building from existing topologies is rather coarse!
>>> CHARMM and GROMOS follow very different parametrization protocols, so if a systematic analysis has been done, in the context of the relative accuracy of the parent force fields, I would really like to see the results.  I think that would be a very valuable effort.
>> Yes CGgenFF, it builds from building blocks and not clear to me how it adjusts the charges … but no QM!
>>> 
>>> Note that at least CGenFF gives penalty scores for all parameters that it provides the user, specifically telling which parameters will require additional work.
>> How does it determine them?
>> No penalty does not guaranty good parameters but small expected deviation from existing topology …
>>> 
> 
> The answers to your questions above are published (particularly the second paper):
> 
> http://dx.doi.org/10.1021/ci300363c <http://dx.doi.org/10.1021/ci300363c>
> http://dx.doi.org/10.1021/ci3003649 <http://dx.doi.org/10.1021/ci3003649>
> 
> -Justin
> 
>>>> In short: You need an experienced modeller to help you “validating” your topology.
>>>> 
>>> 
>>> Agreed 100%.  There is no black box method that is perfect or can be trusted implicitly.  Some are better than others, but force fields are as much an art as they are a science.  A perfect, hands-off method for parametrization of any molecule is, at present, untenable.
>>> 
>>> -Justin
>>> 
>>>> X-
>>>> 
>>>>> On 12 Jul 2016, at 14:40, David van der Spoel <spoel at xray.bmc.uu.se> wrote:
>>>>> 
>>>>> On 12/07/16 13:47, Justin Lemkul wrote:
>>>>>> 
>>>>>> 
>>>>>> On 7/11/16 9:52 AM, ALEXANDER DHALIWAL wrote:
>>>>>>> Dear GROMACS users,
>>>>>>> 
>>>>>>> I am pioneering the use of GROMACS in my lab to supplement some of our
>>>>>>> experimental research. I have generated some topologies from the
>>>>>>> Automated
>>>>>>> Topology Builder (ATB), but I am unsure whether or not to trust the files
>>>>>>> provided by this service. I am only an undergrad, so I would not feel
>>>>>>> comfortable asking my supervisor to invest thousands of dollars into a
>>>>>>> program such as Gaussian09 to validate these topologies. Does this
>>>>>> 
>>>>>> One would not use Gaussian to validate ATB topologies.  One would
>>>>>> generally *start* with a QM calculation to get charge distributions,
>>>>>> then validate against other data.  The problem with the GROMOS force
>>>>>> field is that there is little connection between QM calculations and the
>>>>>> final topologies.  I have posted at length on this topic just within the
>>>>>> last few days; please check the archive.
>>>>>> 
>>>>>>> community trust the outputs of ATB and, if not, could you provide me with
>>>>>>> suggestions as to how I may validate my topologies given my
>>>>>>> restraints? Any
>>>>>>> advice would be much appreciated.
>>>>>>> 
>>>>>> 
>>>>>> It depends on how complex the molecules are.  GROMOS parametrization is
>>>>>> empirical; existing building blocks are put together to yield a
>>>>>> molecule, and any unknown groups or strange linkages are explicitly
>>>>>> parametrized using model compounds.  I don't recall all the guts of what
>>>>>> ATB does (I haven't used the GROMOS force field in a long time) but I
>>>>>> believe it is doing this, coupled with a quick QM calculation for charge
>>>>>> refinement in the case that the constituent groups are not easily looked
>>>>>> up from an existing database).  In general, the topologies from ATB are
>>>>>> significantly better than from, e.g. PRODRG, but the skeptic/force field
>>>>>> purist in me never trusts a black box.  The problem, when it comes to
>>>>>> ligands/drugs is lack of target data.  For small molecules, there are
>>>>>> thermodynamic properties that one can look at.  For more complex things
>>>>>> like drugs, you might get lucky and have something like a logP tabulated
>>>>>> somewhere, but such data can often be difficult or impossible to obtain.
>>>>>> 
>>>>>> -Justin
>>>>>> 
>>>>> http://virtualchemistry.org provides validated topologies for about 150 compounds, that is force fields have been tested by running liquid simulations.
>>>>> 
>>>>> 
>>>>> --
>>>>> David van der Spoel, Ph.D., Professor of Biology
>>>>> Dept. of Cell & Molec. Biol., Uppsala University.
>>>>> Box 596, 75124 Uppsala, Sweden. Phone:	+46184714205.
>>>>> spoel at xray.bmc.uu.se    http://folding.bmc.uu.se
>>>>> --
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>>>> 
>>> 
>>> --
>>> ==================================================
>>> 
>>> Justin A. Lemkul, Ph.D.
>>> Ruth L. Kirschstein NRSA Postdoctoral Fellow
>>> 
>>> Department of Pharmaceutical Sciences
>>> School of Pharmacy
>>> Health Sciences Facility II, Room 629
>>> University of Maryland, Baltimore
>>> 20 Penn St.
>>> Baltimore, MD 21201
>>> 
>>> jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu> <mailto:jalemkul at outerbanks.umaryland.edu <mailto:jalemkul at outerbanks.umaryland.edu>> | (410) 706-7441
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>> 
> 
> -- 
> ==================================================
> 
> Justin A. Lemkul, Ph.D.
> Ruth L. Kirschstein NRSA Postdoctoral Fellow
> 
> Department of Pharmaceutical Sciences
> School of Pharmacy
> Health Sciences Facility II, Room 629
> University of Maryland, Baltimore
> 20 Penn St.
> Baltimore, MD 21201
> 
> jalemkul at outerbanks.umaryland.edu | (410) 706-7441
> http://mackerell.umaryland.edu/~jalemkul
> 
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