How to parameterise ligands

General Tips

Amber

Practical tips by Junmei Wang copied from the Amber Manual:

1. For the input molecules, make sure there are no open valences and the structures are reasonable. All hy- drogen atoms must be present. Antechamber doesn’t know what to do with metal ions (see the MCPB.py program for that), or for other non-organic elements such as Boron. Look at the $AMBERHOME/dat/leap/- parm/gaff.dat file to see what sorts of atomic environments are supported.
2. The Antechamber package produces two kinds of messages: error messages and informative messages. In- formative messages begin with "Info:" and may be safely ignored, but they may be helpful for understanding and troubleshooting antechamber. For example: "Info: Bond types are assigned for valence state 1 with penalty of 1". Messages beginning with "Fatal Error!" or "Error:" indicate a problem. Some such messages may mention likely causes or contain suggested workarounds, but all such messages provide clues. Apply common sense and the scientific method to troubleshoot. Typical first steps are to verify input files and to search the AMBER Mail Reflector for similar reported problems. Additional steps are described below.
3. Failures are most often produced when antechamber infers an incorrect connectivity. In such cases, you can revise by hand the connectivity information in "ac" or "mol2" files. Systematic errors could be corrected by revising the parameters in $AMBERHOME/dat/antechamber/CONNECT.TPL.
4. It is a good idea to check the intermediate files in case of a program failure, and you can run separate programs one by one. Use the "-s 2" flag to antechamber to see details of what it is doing.
5. acdoctor can diagnose many possible problems with input molecules. If you encounter failures when running antechamber programs, it is highly recommended to let acdoctor perform a diagnosis. Run the acdoctor program or use the acdoctor mode in program antechamber; the latter is controlled by option ’-dr’ and is on by default.

Gromacs

CHARMM

Make sure you have the most recent forcefield from here

You are directed to How to prepare a system

SwissParm

Go to SwissParam

First initiate topol.top using pdb2gmx

gmx pdb2gmx -f recpt.pdb -ignh

Remove [atomtypes]/[pairtypes] in itp to create LIG.itp

Copy [atomtypes]/[pairtypes] directly to topol.top

; Include forcefield parameters
#include "charmm27.ff/forcefield.itp"

### Insert Here ###
[ atomtypes ] 
...
[ pairtypes ] 
...
; Include lig topologies
#include "LIG.itp"
### Insert Here ###

; Include chain topologies
#include "topol_Protein_chain_A.itp"

Copy LIG coordinates to conf.gro manually

gmx editconf -f lig1.pdb -o LIG.gro

Good to go

CGenFF

Read this tutorial by Justin

CGenFF Server

Go to CGenFF. Upload mol2 to obtain str files (and maybe additional parameters in parm file)

If it does not work, check:

1. Add hydrogens. You can use Avogadro or Chimera.
2. Make sure your input is a Sybyl mol2. Use Openbabel or save by Chimera.
3. Check all the connectivity
4. Bond orders and fixed using sort_mol2_bonds.pl (provided by Justin)

charmm2gmx

Also at Mackerell's page, get a python script converting CHARMM str to Gromacs files.

python cgenff_charmm2gmx.py LIG lig.mol2 lig.str charmm36-feb2021.ff

If it does not work, check:

1. Version of your CHARMM forcefield
2. Version of your python and networks package. python2+nx1.1 or python3+nx1.1 or python2+nx2.3
3. To avoid duplicated parameters, do NOT select the 'Include parameters that are already in CGenFF' option when uploading a molecule into CGenFF

Easy install prerequisites:

conda create -n charmm2gmx python=2.7
conda activate charmm2gmx
pip install networkx==1.11

Create your topol.top

First initiate topol.top using pdb2gmx

gmx pdb2gmx -f recpt.pdb -ignh

Add LIG.itp to topol.top

Amber

References: [1] [2] [3] [4]

antechamber -i lig.mol2 -fi mol2 -o LIG.mol2 -fo mol2 -j 4 -at gaff -c bcc -nc 0
parmchk -i LIG.mol2 -f mol2 -o LIG.frcmod
tleap -s -f tleap.all
acpype -p com_solvated.top -x com_solvated.crd -b complex

You can find the tleap.all here.