ADL: covalent docking with Autodock - RMSD calculation

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ADL: covalent docking with Autodock - RMSD calculation


I did some covalent dockings with Autodock, using the flexible side chains
I ran into different problems, because the atoms are renamed, and
re-organised, so it makes it impossible to calculate RMSD values.

Also, in the example given when one downloads the covalent docking tutorial
and script files, the RMSD printed in the output is -nan.

So, how is it possible to get a RMSD value ?

Finally, in the same scripts, a README.txt file is given (I copied its
content at the end of this message), with the instructions for running
covalent docking. In that file, it is written :

"Also, in order to include the ligand atoms in the calculation of RMSD and
clustering, the following parameters need to be added:

    rmsdatoms all

but adding this keyword gives the following message :

"autodock4: FATAL ERROR: DPF> rmsdatoms all

autodock4: ERROR: Unrecognized keyword in docking parameter file.

autodock4: Unsuccessful Completion."

so apparently this option does not even exist.

Did someone ran into the same problem as me ? And most important, could
anyone provide a solution ?

All the best,

README.txt file :

This tutorial describes how to apply the 'flexible side chain' covalent
docking as described in the paper:

   "Covalent docking using autodock: Two-point attractor and flexible side
chain methods"

If you use this method, please cite the paper.
Happy dockings!

- Python  >=2.6
- OpenBabel Python bindings
   (On Debian/Ubuntu derivatives, it can be installed with "apt-get install

- Basic experience with docking with AutoDock

- Copy the directory 'adcovalent' in a location that is accessible from the
user (i.e., '~/local/adcovalent').


The preparation code is used to generate the geometry of the ligand
covalently bound to the
residue. Once the ligand initial coordinate is generated, the PDBQT files of
the receptor and
flexible ligand need to be generated using script
in AutoDockTools.

The directory '3upo_test' contains an example case of a ligand ready to
The following examples assume a terminal opened in that location.

1. Generate the alignment
The input ligand structure must be modeled with a portion of the alkylated
residue already present,
i.e. for a ligand bound to a serine:


the ligand structure to process should be:

         LIGAND-O-C [MOL2]

where C and O are the two atoms that are going to be used for the alignment.
More in general:

        0. Initial configuration

           [L]----A      I---J--[R]

        1. Translate [L] to overlap A->I

           [L]----A  ->  I---J--[R]

        2. Rotate [L] around the normal of plane (B,A,J) to overlap B->J


The alignment could be skipped if the ligand is already attached to the
receptor structure
(i.e., a re-docking experiment from a PDB is going to be perfoemd).

To perform the alignment, a receptor file and a residue name (Chain:ResNum)
be specified, then a ligand file and an alignment criterion.

The ligand alignment can be defined in two ways. The first is by specifying
the atom indices in the ligand file (i.e., first and second atoms):

    python  ~/local/adcovalent/ --ligand ligand.mol2 \
                  --ligindices 1,2\
                  --receptor 3upo_protein.pdb\
                  --residue B:SER222\
                  --outputfile ligcovalent.pdb

2. Generate PDBQT files
The standard PDBQT files for AutoDock need to be generated for both the
receptor structure. The standard ADT scripts
are going to be used, assuming that $MGLROOT is the path where ADT has been

*** NOTE: if a covalent ligand is already bound to the residue in the
protein structure, it must be removed! ***

$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
3upo_protein.pdb -A hydrogens
       [ this generates the file "3upo_protein.pdbqt" ]

and the covalent ligand that has been aligned:

$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
       [ this generates the file "ligcovalent.pdbqt" ]

3. Generate flexible/rigid PDBQT files
The PDBQT files are going to be used to generate the rigid and flexible
components that are going to be used
for the docking.
First, the receptor is processed to extract the rigid part by specifying
which residue is going to be made flexible:

$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
3upo_protein.pdbqt -s 3upo_protein:B:SER222
       [ this generates the files "3upo_protein_rigid.pdbqt" and
"3upo_protein_flex.pdbqt" ]

The same thing is going to be done for the processed ligand:

$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
ligcovalent.pdbqt -s ligcovalent:B:SER222
       [ this generates the files "ligcovalent_rigid.pdbqt" and
"ligcovalent_flex.pdbqt" ]

NOTE: if the ligand has not been prepared in step 1, make sure that all
atoms in the ligand have the poper residue id
corresponding to the residue modified (i.e., Ser222A).

4. Generate GPF and DPF files
The parameter files for the actual calculation are going to be generated.
The GPF for AutoGrid is generated with:
$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
                -x ligcovalent_flex.pdbqt\
                -l ligcovalent_flex.pdbqt\
                -y -I 20\
                -o 3upo_priotein.gpf

The DPF for AutoDock is generated with:

$MGLROOT/MGLToolsPckgs/AutoDockTools/Utilities24/ -r
                -x ligcovalent_flex.pdbqt\
                -l ligcovalent_flex.pdbqt\
                -o ligcovalent_3upo_protein.dpf\
                -p move='empty'

This command instructs the script to dock the covalent ligand as a flexible
residue and ignore any 'true' ligand ("move='empty'"). To do this,
an empty file must be created, and it can be done with the following Unix

    touch empty

Also, in order to include the ligand atoms in the calculation of RMSD and
clustering, the following parameters need to be added:

    rmsdatoms all

which will include flexible residue (and ligand) atoms in the RMSD
 Finally, the DPF file must be manually edited to set the appropriate energy
model so that the docking score corresponds to the interaction between
the flexible residue (the ligand) and the rigid receptor. For this, the

    unbound_model bound

must be replaced with:

    unbound_energy 0.0

5. Run AutoGrid and AutoDock
Both programs can be executed using the standard procedure:

    autogrid4 -p 3upo_priotein.gpf -l 3upo_priotein.glg
    autodock4 -p ligcovalent_3upo_protein.dpf -l

The output generated at each step of the process is available in the
directory '3upo_test/output'.

Sent from:

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