[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
>>> receptor but that is not the biological answer.
>> If your system is not behaving in the biologically-dictated manner, I
>> 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
> 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
>> moleculetypes, and again, if you're trying too hard to force something
>> 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
>>> 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
>> 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.:
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.
>> Could anyone help me?
>> Thank you in advance
> 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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Justin A. Lemkul
ICTAS Doctoral Scholar
Department of Biochemistry
jalemkul[at]vt.edu | (540) 231-9080
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