Use case 3: covalent ligand with rigid receptor
It is assumed that you downloaded and installed MGLTools2 and
for this tutorial and that agfr, adfr,
about and pmv2 are in your PATH environment
Generate the target file (i.e. affinity maps and
We want to re-dock the native covalent ligand of 3c9w. Both,
the receptor (3cw9.pdbqt) and ligand (3c9w_ligandWithSideChain_random.pdbqt) have been prepared for docking (i.e. PDBQT
files are available).
For covalent docking, the prepared receptor and covalent
ligand need to share 3 atoms as sown below. These atoms are used to transform the
ligand into place with respect to the receptor to create the covalent bond.
agfr -r 3c9w.pdbqt -b
user 28.565 6.329 6.985 22.5 22.5 22.5 -c 1593 1596 -t 1591 -x A:CYS164 -o
- In this example we specify
the box placement and size manually to illustrate this capability. Note
that this is the only -b/-boxMode option for
which padding is ignored.
- The PDB serial numbers of
the 2 receptor atoms forming the covalent bond are specified using the -c/--covalentBond option. The numbers are the serial codes
appearing in the pdbqt file.
- The third atom defining
the covalent attachment is used to compute the torsion angle of the
covalent bond. It is specified using the -t/--covalentBondTorsionAtom
- The -x/--covalentResidues option allows to limit the traversal
of the receptor to a list or residues. This is needed sometimes as covalent
residues can create bonds with the receptor other than the covalent
attachment and this is the case with the native ligand of 3cw9. When agfr
identifies the sub-tree beyond the covalent bond to find which atoms to
cut out of the receptor for calculating affinity maps, it would include a
large part of the receptor because of the spurious bond the ligand makes
with the receptor and cut out in excess of 1600 atoms. The -x option
prevents this from happening.
More details about running this
commands are available here.
The resulting target file 4EK3_rec_FR_10_82.trg file provides a
description of a rigid receptor suitable for docking (with AutoDockFR) ligands prepared for
AutoDock4 into the binding site of the known ligand. The file can be inspect
using the following command:
Dock a ligand using the generated target file
Here we re-dock a known ligand, that has been randomized
(i.e. its conformation as well as it positions and orientation in the crystal
structure have been randomly modified). This is a proof-of-concept docking
aimed at illustrating the use of adfr and verifying that the docking procedure is able to
reproduce a known result.
3c9w_ligandWithSideChain_random.pdbqt -t 3c9w_cov_cmdline.trg
--jobName covalent -C 1 2 3 --nbRuns
8 --maxEvals 100000 -O --seed 1
Details about this calculation are available here.
- adfr detects and, by default,
will use all the cores on the computer to perform 8 Genetic Algorithms
evolutions, each using up to 200'000 evaluations of the scoring function.
The default number of runs is 50 and each run can use up to 2.5 million
evaluations by default. These parameters are set to lower values for the
tutorial for the docking to terminate faster and to prevent all runs to
converge to the same solution, thus allowing us to illustrate what happens
when multiple docking poses are reported.
- This calculation generates
the following files:
The file can be
inspect using the following command:
Viewing the docking results
Docking Results Object files (.dro) can be opened by pmv2. A group is created
containing the ligand and receptor molecules. Both molecules are displayed and
the inter-molecular hydrogen bonds are displayed.