[gmx-users] RE: gmx-users Digest, Vol 66, Issue 124

Justin A. Lemkul jalemkul at vt.edu
Mon Oct 19 19:02:19 CEST 2009

Thielges, Sabine wrote:
> Thielges, Sabine wrote:
>>> Hi everyone,
>>> I am currently doing a simulation which involves a dopamine receptor 
>>> placed in a POPC membrane and an agonist or antagonist in the active 
>>> site. The ligand was placed by VS and is closed to what the biology 
>>> gives. My problem is that the ligand get out of is normal position 
>>> during the simulation. I know it is easier to move the ligand than
> the 
>>> receptor but that is not the biological answer.
>> If your system is not behaving in the biologically-dictated manner, I
> would 
>> guess that whatever parameters you are using are unsuitable.  Which
> force field 
>> are you using, and where did you get the ligand parameters?  How were
> they 
>> validated?
> I am using the force field ffG53a6 for both, it was the one recommended
> by the membrane tutorial.  the ligand parameters were created using the
> web site PRODRG which generates a drggmx.itp type that I have to
> manually modify since all the atoms types are not in the protein ff that
> I am using. Not the best but I didn't know which other ff would be
> appropriate for both receptor and ligand.

You have to do substantially more than just change the atom types.  You have to 
change the charges and charge groups, too.  I have found that PRODRG doesn't do 
such a great job with charges, and it does have a very profound impact on the 
results.  Validation would also be nice, but usually functional group parameters 
are transferable within 53a6, so I have found.  If you're dealing with any sort 
of non-protein functional groups (esters, ketones, thioesters, etc) then I would 
think you would have to do the extra work of demonstrating your parameters are 
valid, as well.

>>> I would like to know if there is a way to fix the ligand so that the 
>>> receptor would be force to adapt around it and not the inverse. There
>>> is know Hbonds with specific amino acid is it possible to add this 
>>> information in the run.
>> You could implement distance restraints, but that would require merging
> the 
>> moleculetypes, and again, if you're trying too hard to force something
> to 
>> Happen, I would seriously question the accuracy of what you're doing.
> I have the same doubted, but I know for the receptor it self I had to do
> the same thing. I added position restraints that I gradually decreased
> from 1000 to 0 by doing few small MD and then I could do the real MD
> without any. My idea was to find a way to do the same thing with the
> drug nut I couldn't find any.
> How can I merge the 2 molecules since my ligand is not a protein and
> pdb2gmx doesn't work when I have it in my structure.pdb?

Modify the topology by hand to include the ligand under the Protein moleculetype 
definition (i.e., by adding to the atoms, bonds, angles, etc directives).  I 
would still argue that this is an inappropriate way to address the problems 
you're having.

>>> I tried so far to use position restraint in my ligand.itp
>>> [ position_restraints ]
>>> ;  i funct       fcx        fcy        fcz
>>>    1    1       10000      10000      10000
>>>    3    1       10000      10000      10000
>>>    4    1       10000      10000      10000
>>>    5    1       10000      10000      10000
>>>    6    1       10000      10000      10000
>>>    8    1       10000      10000      10000
>>>    9    1       10000      10000      10000
>>>   10    1       10000      10000      10000
>>>   11    1       10000      10000      10000
>>>   12    1       10000      10000      10000
>>>   13    1       10000      10000      10000
>>> But it didn't have any effect on the final MD simulation of 10 ns. At 
>>> he end the ligand was completely out of the site.
>> Then you didn't actually apply position restraints.  Did you use
> appropriate 
>> define" statements in the .mdp file (if necessary)?
> I know that I don't because if I create a posre.itp for the drug like I
> do for the receptor and that I define it in my .mdp, I got a message
> error saying that I define atoms in the wrong molecule. Because the
> ligand is not the protein.

Well, if you didn't apply position restraints, then you can't complain that 
they're not working :)  The default output of genrestr is posre.itp, which 
(unfortunately?) is the same name as that of the PR file for the protein.  You 
would probably want to create a "ligand_posre.itp" file, and #include it after 
you've defined the ligand in the topology, i.e.:

#include "ligand.itp"

#include "ligand_posre.itp"

I would still worry more about the parameters used (or even the starting 
configuration generated - docking is not always perfect!) before attempting any 
of the hacks I've described above.


> Thanks again for your help.
> Sabine
>> -Justin
>> Could anyone help me?
>> Thank you in advance
>> Sabine
>> ========================================
> Justin A. Lemkul
> Ph.D. Candidate
> ICTAS Doctoral Scholar
> Department of Biochemistry
> Virginia Tech
> Blacksburg, VA
> jalemkul[at]vt.edu | (540) 231-9080
> http://www.bevanlab.biochem.vt.edu/Pages/Personal/justi
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Justin A. Lemkul
Ph.D. Candidate
ICTAS Doctoral Scholar
Department of Biochemistry
Virginia Tech
Blacksburg, VA
jalemkul[at]vt.edu | (540) 231-9080


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