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"
#ifdef POSRES_LIGAND
#include "ligand_posre.itp"
#endif
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.
-Justin
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
http://www.bevanlab.biochem.vt.edu/Pages/Personal/justin
========================================
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