[gmx-users] Using ATB to generate valid topologies

[Justin Lemkul]

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

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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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