Difference between revisions of "Pose Reproduction SB2024 V1 DOCK6.10 A"

Revision as of 14:43, 21 February 2024

!!!!!!Under Construction!!!!!!

The purpose of this tutorial is to develop a uniform method to test pose reproduction across the Rizzo lab with the DOCK software. Note any data in this tutorial is solely for the purpose of example.

I.Introduction

-Pose reproduction is an experiment which tests a docking programs ability to predict the bound pose of a ligand to a receptor (typically a protein). An experimental structure of a protein-ligand complex is converted into 2 separate files, 1 for ligand and 1 for receptor. The docking program then predicts the binding orientation that is most energetically favorable. In the case of DOCK6, the ligand is flexibly docked with the Anchor & Grow algorithm to a rigid receptor.

-The RMSD between the docked poses and experimental pose are measured. We consider RMSD < 2 angstroms an accurate prediction. There are 3 outcomes we classify.

1) Success - The best scoring pose is < 2 angstroms

2) Scoring Fail - A pose < 2 angstroms was sampled but did not score best

3) Sampling Fail - No pose < 2 angstroms was sampled

II.Necessary files

Scripts to run Pose Reproduction in batch mode are found at:

    https://github.com/rizzolab/Benchmarking_and_Validation

This tutorial uses Single Grid Energy as the primary score for docking. This is the typical score used by the Rizzo Lab for this purpose and for generating poses in Virtual Screening. Thus, grid files are required. The receptor mol2 is only necessary for visualization purposes. The list of necessary files are:

    ${pdb_id}.lig.am1bcc.mol2
    ${pdb_id}.rec.clust.close.sph
    ${pdb_id}.rec.clean.mol2
    ${pdb_id}.rec.bmp
    ${pdb_id}.rec.nrg

All necessary files for different versions of our test set are available for download at:

    https://ringo.ams.stonybrook.edu/index.php/Rizzo_Lab_Downloads

To (re)create a testset using Rizzo Lab Protocols:

    https://ringo.ams.stonybrook.edu/index.php/Test_Set_Tutorial_V1

III.Docking molecules

In 001.submit_dock.sh edit the following variables:

     system_file="List of PDB codes in a file delimited by line"
     testset="Path to necessary files for docking (section above)"
     dock_dir="Uppermost directory of DOCK6 executable"

Additionally other variables can be changed in 001.submit_dock.sh :

    condition="Unique name given to each experiment output - otherwise 'Default' "
    seed="Random seed - otherwise '0' "

Submit the job after specifying partition and wall clock criteria. Typically ~2 minutes per system per core is sufficient.

    sbatch 001.submit_dock.sh

This calls the script FLX.sh for each system which writes a dock input file and then immediately calls DOCK6.

A separate dock input file is written for each system. Below is the input file for DOCK6.10, but best practice would be to develop an input file in FLX.sh by first interactively creating an input file with the version of DOCK being used. This will prevent any changes in queries being overlooked:

conformer_search_type                                        flex
write_fragment_libraries                                     no
user_specified_anchor                                        no
limit_max_anchors                                            no
min_anchor_size                                              5
pruning_use_clustering                                       yes
pruning_max_orients                                          1000
pruning_clustering_cutoff                                    100
pruning_conformer_score_cutoff                               100.0
pruning_conformer_score_scaling_factor                       1.0
use_clash_overlap                                            no
write_growth_tree                                            no
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file              /${testset}/${system}/${system}.lig.gast.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               yes
use_rmsd_reference_mol                                       yes
rmsd_reference_filename       /${testset}/${system}/${system}.lig.gast.mol2
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file             /${testset}/${system}/${system}.rec.clust.close.sph
max_orientations                                             1000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
bump_filter                                                  no
score_molecules                                              yes
contact_score_primary                                        no
grid_score_primary                                           yes
grid_score_rep_rad_scale                                     1
grid_score_vdw_scale                                         1
grid_score_es_scale                                          1
grid_score_grid_prefix        /${testset}/${system}/${system}.rec
minimize_ligand                                              yes
minimize_anchor                                              yes
minimize_flexible_growth                                     yes
use_advanced_simplex_parameters                              no
minimize_flexible_growth_ramp                                yes
simplex_max_cycles                                           1
simplex_score_converge                                       0.1
simplex_initial_score_coverge                                5
simplex_cycle_converge                                       1.0
simplex_trans_step                                           1.0
simplex_rot_step                                             0.1
simplex_tors_step                                            10.0
simplex_anchor_max_iterations                                500
simplex_grow_max_iterations                                  250
simplex_grow_tors_premin_iterations                          0
simplex_random_seed                                          $seed
simplex_restraint_min                                        no
atom_model                                                   all
vdw_defn_file                                                
/gpfs/projects/rizzo/ccorbo/DOCK_Builds/dock6.10_mpi/parameters/vdw_AMBER_parm99.defn 
flex_defn_file                                               
/gpfs/projects/rizzo/ccorbo/DOCK_Builds/dock6.10_mpi/parameters/flex.defn
flex_drive_file                                              
/gpfs/projects/rizzo/ccorbo/DOCK_Builds/dock6.10_mpi/parameters/flex_drive.tbl
ligand_outfile_prefix                                        ${condition}_$seed
write_orientations                                           no
num_scored_conformers                                        1000 
rank_ligands                                                 no

When docking is completed you will have a separate directory for each system. In each directory will be the input file, output file, and mol2 of docked results. If condition was "Default" and seed was "0", the file will be named:

    ${pdb_id}/Default_0_scored.mol2

IV.Pose Reproduction Analysis

Next run a script which calculates outcomes. This script is compatible with python 2.

    module load py/2.7.15 

    python calculate_dock6.results.py ${condition}_${seed} ${system_file}
    
    e.g.: python calculate_dock6.results.py Default_0 clean.systems.all

In the below image, the systems "1KIJ","1QCA","2AA2" did not successfully dock. There were 1,279 systems in the list provided. The raw number of systems and percentage for "Success", "Score Fail" and "Sample Fail" are given. Incomplete docked systems are counted as Sample Fails.

Output from calculate_dock6.results.py shows systems which didn't dock and Success and Fail rates

-SEE README FILE IN GIT REPO FOR ADDTIONAL DETAILS THAT MAY NOT BE COVERED HERE

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Tutorial Written By: Christopher Corbo, Rizzo Lab, Stony Brook University (2024)

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