Use case 2: receptor with flexible side chains

 

It is assumed that you downloaded and installed MGLTools2 and the data for this tutorial and that agfr, adfr, about and pmv2 are in your PATH environment variable.

1.   Generate the target file (i.e. affinity maps and translational points)

In this case we have a receptor we want to dock against (4EK3_rec.pdbqt) and a known ligand for this receptor (4EK4_lig.pdbqt). Both molecules have been prepared for AutoDock4 (i.e. exist in the PDBQT format).

agfr -l 4EK4_lig.pdbqt -r 4EK3_rec.pdbqt -P 7.0 -f A:ILE10,PHE82 -o 4EK3_rec_FR_10_82

  1. agfr uses the known ligand to build a box covering the ligand with padding 7.0 which is specified using the -P/--padding option
  2. it then performs AutoSite on this box to identify binding pockets (within this box) and merges all fills points to create translational points for AutoDockFR
  3. the -f/--flexRes option is used to specify flexible side chains. In this case 2 side chains will be made flexible: ILE10 and PHE82 in chain A. For multiple chains separate the selection string using a semi-colon ";" i.e. "A:ILE10;B:ARG89". Making side chains flexible will prevent atoms from the side chain and the C-alpha atom of these amino acids from contributing to the potentials on the grid points.
  4. By default, AutoGrid4 affinity maps are generated for all atom types.

 

More details about running this command 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:

about 4EK3_rec_FR_10_82.trg

details

2.   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.

adfr -l 4EK4_random.pdbqt -t 4EK3_rec_FR_10_82.trg --jobName flexRes --nbRuns 8 --maxEvals 20000 -O --seed 1

Details about this calculation are available here.

 

  1. adfr detects and, by default, will use all the cores on the computer to perform 8 Genetic Algorithms evolutions, each using up to 200000 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.
  2. This calculation generates the following files:

4EK4_random_flexRes_summary.dlg
4EK4_random_flexRes_out.pdbqt
4EK4_random_flexRes.dro

The file can be inspect using the following command:

about 4EK4_random_flexRes.dro

details

3.   Viewing the docking results

Docking Results Object files (.dro) can be opened by Pmv2. A group is created containing the ligand and receptor molecules. For docking with flexible side chains, a selection is created for the receptor flexible side chains. Both molecules are displayed and the inter-molecular hydrogen bonds are displayed. If there is more than one solution, the group can be scrolled using the mouse middle button or the arrow keys on the keyboard. The space bar on the keyboards allows toggling on and off an animation flipping between the solutions. The Home and End keys on the keyboard will jump to the first and last solutions respectively.

pmv2 4EK4_random_flexRes.dro