(unknown charset) Re: [AMBER] Ligand modifying softwares.

From: (unknown charset) Luka Bilić <Luka.Bilic.irb.hr>
Date: Fri, 19 Jan 2018 10:28:01 +0100

I don't think there's a streamlined program for that.
If there is I don't know about it (probably because I didn't need one
yet). If you need to go through more than 10-20 different ligands
don't read further, this message won't be of any help :)

If you have a little number of ligands this might be of help.

What I do when I need to put different ligand in the enzyme is a step
by step process.
It's long and boring (and I bet there is a more elegant way to do that
:) but here's what I do)

PDB file containing your enzyme+ligand complex is modified so that the
ligand contains only skeleton of atoms that are the same within all
the compounds of your interest. All other atoms are deleted from PDB.
To see which atoms to remove help yourself with VMD or Pymol
(visualization softwares that read .pdb files)

Say you want to simulate toluene, benzene, benzoic acid, some benzoic
esters, maybe benzoic chloride in your enzyme or protein binding pocket.
And lets say you have a benzene molecule in the binding site of your
PDB crystal structure but you want to have a toluene based derivates.
Tleap this enzyme with appropriate force fields (FF14SB and gaff - or
whichever you choose) - all errors you get now are irrelevant as long
as you get PDB with hydrogens on your benzene and nothing goes really
wrong. Don't solvate anything yet.

Turn/Change one hydrogen of benzene into carbon atom (naming of ligand
atoms must be consistent with gaff or gaff2, whichever forcefield you
choose to use for your ligands) and remove all non-carbon atoms from
your ligand. Fix naming of residues or atoms manually it there's some
trouble with that.

Now to get structures you want within the enzyme you first need to put
them there in the PDB where your toluene skeleton is. So how to do it?

You can use QM software like Gaussian to get optimized starting
structures of your "toluene" based compounds. Or whichever ligand you
work with, but this is a simple example with toluene based compounds.

Antechamber can turn your .log into .mol2
You must do RESP charges (and this is the most important thing because
bad charges will mess up your simulations more than a bad angle bend -
but I guess this is case specific). So read the manuals about RESP
fitting and/or ask somebody who know this to help you out.

Now you must generate your .lib and .frcmod files for your toluene,
benzoic acid, benzoic ester and benzoic chloride using <appropriate
molecule>.mol2 and following appropriate RESP fitting for that
"molecule". (Amber tutorials can help you on how to do it and you can
find additional info on various other sites)

So you have your:
BEZ.frcmod BEZ.lib (benzene)
TOL.frcmod TOL.lib (toluene)
BEC.frcmod BEC.lib (benzoic acid)
BEE.frcmod BEE.lib (benzoic ester)
BCL.frcmod BCL.lib (benzoic chloride)

Now copy paste your enzyme-ligand-skeleton.pdb into enzymeBEZ.pdb,
enzymeTOL.pdb etc.

Change the name of your ligand (say it was named LIG) into appropriate
name (TOL, BEC or whatever is the one you need - and don't forget to
remove the extra carbon for the benzene if you have toluene skeleton
in the enzyme, also you don't have to add any atoms. Tleap will do it
by reading .lib files for your ligand)

Now tleap each of these enzyme+appropriate-Ligand.pdb with appropriate
.frcmod and .lib file. If your naming was consistent you should be
fine and without any errors.

This will give you your desired complexes. (H++ them to get
protonation sites ready and then solvate your new enzyme-ligand
complexes)

And to correct for potential issues with the structure (atoms too
close or something like that) equilibrate your system after solvation.
(How you choose to equilibrate is really up to you. But the more
careful approach you chose the better :) )

Then do MD or QM/MM or whatever you wanted to do.

I know this is long, boring and maybe even impractical if you have ...
50, 100 or 1000 compounds to test for.
But if you have like 5-10 of them this "manual" way is just fine.
Maybe boring, a bit time consuming and definitely not elegant but it
works as long as you have all the parameters for your ligand and you
did a good job with RESP fitting.


Citiram Vatsal Purohit <vatsal.purohit15.gmail.com>:

> Hi,
>
> Could you recommend some graphic interfaces to modify ligands to add
> derivative groups to them within an enzyme active site. I'm looking to run
> an MD simulation with different modified ligands in an enzyme.
>
> Regards,
> Vatsal
> _______________________________________________
> AMBER mailing list
> AMBER.ambermd.org
> http://lists.ambermd.org/mailman/listinfo/amber
>



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Received on Fri Jan 19 2018 - 01:30:03 PST
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