2018 DOCK tutorial 2 with PDBID 1C87

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For additional Rizzo Lab tutorials see DOCK Tutorials. Use this link Wiki Formatting as a reference for editing the wiki. This tutorial was developed collaboratively by the AMS 536 class of 2018, using DOCK v6.8 and it shows how to dock a ligand into a receptor.

I. Introduction


DOCK is a molecular docking program used in drug discovery. It was developed by Irwin D. Kuntz, Jr. and colleagues at UCSF (see UCSF DOCK). This program, given a protein binding site and a small molecule, tries to predict the correct binding mode of the small molecule in the binding site, and the associated binding energy. Small molecules with highly favorable binding energies could be new drug leads. This makes DOCK a valuable drug discovery tool. DOCK is typically used to screen massive libraries of millions of compounds against a protein to isolate potential drug leads. These leads are then further studied, and could eventually result in a new, marketable drug. DOCK works well as a screening procedure for generating leads, but is not currently as useful for optimization of those leads.

DOCK 6 uses an incremental construction algorithm called anchor and grow. It is described by a three-step process:

  1. Rigid portion of ligand (anchor) is docked by geometric methods.
  2. Non-rigid segments added in layers; energy minimized.
  3. The resulting configurations are 'pruned' and energy re-minimized, yielding the docked configurations.


In this tutorial we will use PDB code 1C87, which is the crystal structure of protein tyrosine phosphatase 1B complexed with 2-(oxalyl-amino-4,7-dihydro-5H-thieno[2,3-C]pyran-3-carboxylic acid.

Organizing Directories

We are going to create and organize directories so it would be easier for us to find or identify files in each directory.


II. Preparing the Receptor and Ligand

Download the PDB File (1C87)

We are going to the PDB website (https://www.rcsb.org/) to download 1C87.pdb file and transfer this pdb file to your directory. First, open Chimera and load 1C87.pdb file. Remove the receptor and save ligand (not HOH) in mol2.format. "mol" format shows types of bonds whether it is single or double bond. Then, add H on receptor and ligand by clicking Tools and Structure Editing and save the files. (NOTE: when you add H on ligand, make the charge -1. Check the article that is related to pdb file to decide whether it should be pronated or depronated.) Lastly, open the receptor file and click Surface Editing and write DMS file. Make sure to save all files. So far, we will have these files ready.

1c87.pdb                      lig_withH_charge_1c87.mol2     noh_receptor_1c87.mol2
lig_withH_1c87.mol2    noh_lig_1c87.mol2                     rec_withH_1c87.mol2

After saving these two files with H, transfer files into 001.files directory:

 scp -r ./*1c87* username@login.seawulf.stonybrook.edu:/gpfs/projects/AMS536/2018/your_directory_name/001.files

III. Generating Receptor Surface and Spheres

Generating the Receptor Surface

Make sure sphere directory is created and open the directory:

mkdir 002.surface
cd 002.surface

Open Chimera and load the receptor surface:

Load the receptor (noh_receptor_1c87.mol2) file, which is located in the 001.files directory. Go to Action -> Surface -> Show and it will show the surface receptor. Next, save a DMS file as noh_surface_rec.dms by clicking Tools -> Structure editing -> Write DMS.

Creating Spheres We are going to create spheres by using the Sphgen program, which is a sphere generation program in Dock.

1. Create an input file


Copy this following script in INSPH input file.


The first line ./noh_surface_rec.dms specifies the input file. R means that spheres generated will be outside of the receptor surface. X specifies all the points will be used. 0.0 is the distance in angstrom and it will avoid steric clashes. 4.0 is the maximum surface radius of the spheres and 1.4 is the minimum radius in angstroms.The last line 1c87.spheres.sph creates the file that has clustered spheres.

2. Run the Sphgen program

sphgen -i INSPH -o OUTSPH

-i chooses input file and -o writes toutput file.

3. Open Chimera to visualize the generated spheres Load 1c87.recep.sph file.

File:Generated 1C87 surface spheres.png
The generated 1C87 surface spheres

Now, we are going to select the spheres that is close to the native ligand molecule, which would be within 8.0 angstroms of the ligand.

sphere_selector 1c87.recep.sph ../001.files/lig_withH_charge_1c87.mol2 8.0

1c87.recep.pdbwill be created and load this file in Chimera.

IV. Generating Box and Grid

Enter 003.box-grid directory. Create input showbox.in:


The first line Y creates a box (grid). 8.0 is the box length in angstroms. The last line, 1c87.box.pdb, outputs the box to the file.

Use this input type:

showbox < showbox.in

Now we can visualize the box in Chimera. Load 1c87.box.pdb.

File:Selected spheres with box.png
The selected spheres with box

Then, we will compute the energy grid. Create grid.in file

vi grid.in

Save the output in the file grid.out.

grid -i grid.in > grid.out

Answer the questions:

 compute_grids             yes
 grid_spacing              0.4
 output_molecule           no
 contact_score             no
 energy_score              yes
 energy_cutoff_distance    9999
 atom_model                a
 attractive_exponent       6
 repulsive_exponent        9
 distance_dielectric       yes
 dielectric_factor         4
 bump_filter               yes
 bump_overlap              0.75
 receptor_file             ../001.files/lig_withH_charge_1c87.mol2
 box_file                  ../003.box/1c87.box.pdb
 vdw_definition_file       /opt/AMS536/dock6/parameters/vdw_AMBER_parm99.defn
 score_grid_prefix         grid 

Once completed to answer the questions, it will create two output files: grid.bmp and grid.nrg

V. Docking a Single Molecule for Pose Reproduction


Create min.in file and run dock with this input file.

touch min.in
dock6 -i min.in

Answer the questions like we did above:

 conformer_search_type                                        rigid
 use_internal_energy                                          yes
 internal_energy_rep_exp                                      12
 internal_energy_cutoff                                       100.0
 ligand_atom_file                                             ../001.files/lig_withH_charge_1c87.mol2
 limit_max_ligands                                            no
 skip_molecule                                                no
 read_mol_solvation                                           no
 calculate_rmsd                                               yes
 use_rmsd_reference_mol                                       yes
 rmsd_reference_filename                                     ../001.files/lig_withH_charge_1c87.mol2
 use_database_filter                                          no
 orient_ligand                                                no
 bump_filter                                                  no
 score_molecules                                              yes
 contact_score_primary                                        no
 contact_score_secondary                                      no
 grid_score_primary                                           no
 grid_score_secondary                                         no
 multigrid_score_primary                                      no
 multigrid_score_secondary                                    no
 dock3.5_score_primary                                        no
 dock3.5_score_secondary                                      no
 continuous_score_primary                                     yes
 continuous_score_secondary                                   no
 cont_score_rec_filename                                      ../001.files/lig_withH_charge_1c87.mol2
 cont_score_att_exp                                           6
 cont_score_rep_exp                                           12
 cont_score_rep_rad_scale                                     1
 cont_score_use_dist_dep_dielectric                           yes
 cont_score_dielectric                                        4.0
 cont_score_vdw_scale                                         1
 cont_score_es_scale                                          1
 footprint_similarity_score_secondary                         no
 pharmacophore_score_secondary                                no
 descriptor_score_secondary                                   no
 gbsa_zou_score_secondary                                     no
 gbsa_hawkins_score_secondary                                 no
 SASA_score_secondary                                         no
 amber_score_secondary                                        no
 minimize_ligand                                              yes
 simplex_max_iterations                                       1000
 simplex_tors_premin_iterations                               0
 simplex_max_cycles                                           1
 simplex_score_converge                                       0.1
 simplex_cycle_converge                                       1.0
 simplex_trans_step                                           1.0
 simplex_rot_step                                             0.1
 simplex_tors_step                                            10.0
 simplex_random_seed                                          0
 simplex_restraint_min                                        yes
 atom_model                                                   all
 vdw_defn_file                                                /opt/AMS536/dock6/parameters/vdw_AMBER_parm99.defn
 flex_defn_file                                               /opt/AMS536/dock6/parameters/flex.defn
 flex_drive_file                                              /opt/AMS536/dock6/parameters/flex_drive.tbl
 ligand_outfile_prefix                                        3pgl.min
 write_orientations                                           no
 num_scored_conformers                                        1
 rank_ligands                                                 no
Now, 1c87.min_scored.mol2 will be produced.