Dear RG-members,
During MD simulation, after position restraint MD the covalent bond between the ligand and protein is missing. The ligand is covalently attached to the protein. But, in Gromacs after nvt and npt, the covalent bond is missing followed by a great ligand position displacement. I have tried using Gromos53a6, amber99sb and OPLS/AA. Does anybody face such problems before? Kindly guide me to solve this problem. I want to retain all covalent bonds between the ligand and protein until the end of production MD.
Thanking You
Sincerely
Bikash, Osaka University, Japan
A distance restraint can only be assigned within a single [moleculetype] in any pre-5.0 released version of the code. The development code supports intermolecular restraints but documentation is incomplete.
For a merged [moleculetype], you need to create an .rtp entry for your ligand and merge the chains with pdb2gmx -merge. Then you can assign the distance restraint (please consult the manual, section 4.3.5, where all the necessary details are described an an example is provided). Be sure you are very comfortable with Gromacs file formats and topology organization before attempting this. It can be rather complex to get it all right.
The other big issue is that if the ligand does indeed bond covalently to some amino acid in the protein, then you now have an unnatural amino acid for which you will have to derive parameters. Simply adding a distance restraint might keep some geometry a certain way, but it does not mean the underlying physical model is valid. Given that you'll have to do some parametrization anyway, it may be better to just derive suitable bonded parameters for the modified amino acid residue rather than dealing with restraints. The situation is very complex and needs to be treated with great care.
Make sure whether covalent or non-covalent. As per my knowledge, ligand molecules binds to protein through non-covalent interaction only.
Hi
if you want to keep covalent bod during the molecular dynamics, you should create a restraint between atoms which are participated in the bond, and then define a distance between them.
good luck
marzieh
A distance restraint can only be assigned within a single [moleculetype] in any pre-5.0 released version of the code. The development code supports intermolecular restraints but documentation is incomplete.
For a merged [moleculetype], you need to create an .rtp entry for your ligand and merge the chains with pdb2gmx -merge. Then you can assign the distance restraint (please consult the manual, section 4.3.5, where all the necessary details are described an an example is provided). Be sure you are very comfortable with Gromacs file formats and topology organization before attempting this. It can be rather complex to get it all right.
The other big issue is that if the ligand does indeed bond covalently to some amino acid in the protein, then you now have an unnatural amino acid for which you will have to derive parameters. Simply adding a distance restraint might keep some geometry a certain way, but it does not mean the underlying physical model is valid. Given that you'll have to do some parametrization anyway, it may be better to just derive suitable bonded parameters for the modified amino acid residue rather than dealing with restraints. The situation is very complex and needs to be treated with great care.
Dear Dr. Sahoo,
before to impose constraint in term of covalent interaction I suggest to analyze the charges related to the involved atoms (substrate and interacting atoms). Remember that FFs are often deficient in the description of the atomic charges. Because that the electrostatic term in the energy function is directly proportional to the charges of the interacting atom it is better to correct the original values in the FF with more accurate QM calculations (es NBO). This is a good trick to skip a custom parametrization. Remember that doing this you are not rescaling the values; this need a new parametrization.
Best
Dear Bikash
I made several covalent bonds when I wanted to use haddock server. after docking these complex contains covalent bond, we evaluated the distance between them. i considered all of them have been retained and there weren't any missing.
I suggest you consult with mailing list in the gromacs and ask about it. any way if you have any problems, I am really happy to guide you.
best wishes
marzieh
How you do that in practice depends on the MD package you are using, but in pretty well all of them you can fix virtual bonds. You can even define dummy atoms and fix virtual bonds to these .....
Dear Professor Robert,
Thank you very much for your suggestions. I am thinking to edit my forcefield to recognise the unnatural amino acids. The ligand is covalently bonded to two adjacent amino acids and mimics as an unnatural amino acids. As suggested by Dr. Justin Lemkul, I think distance retrain may not help me defining the molecular conformation in a right way. However, I am failing to edit the FF perfectly. Tried many times, still having some problems in atom types in Gromos53a6-ff. I am hoping to fix the bug soon.
Thanking you
yours sincerely
Sahoo; BR
Osaka University, Japan
Dear Bikash!
If your ligand is indeed covalently bound to an amino acid residue you should define a new molecular topology starting as normal amino acid and ending in that particular ligand of yours. If the atoms involved are more or less standard you can do that on the level of the .rtp file each force field in GroMACS uses. In your input you'll then have to use the name of that new amino acid - ligand molecule you created.
Alternatively you could give Alan Mark's automated topology builder a try, creating that "chimera topology" for you.
Good luck,
Christian.
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