DOCK GA Tutorials

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For this experiment required files will include 2NNQ.lig.mol2

I. Fragment Library Generation for 2NNQ

Fragment Libraries

For this experiment a general fragment library to account for all the possible ligands the GA can produce. A focused Fragment library will not be enough to account for all the possibilities since it is too small of a set of data.

The first step for this experiment is to generate a directory to perform the work in

     mkdir 2NNQ_GA

Go into this new directory and then create another directory that will store all the fragment molecules

     mkdir fraglib

Enter the file directory fraglib

     cd fraglib

Create a new file called 2NNQ.fraglib

     touch 2NNQ.fraglib
     dock6 -i 2NNQ.fraglib

Answer the following prompts using these responses

    conformer_search_type                                        flex
    write_fragment_libraries                                     yes
    fragment_library_prefix                                      2NNQ.fraglib
    fragment_library_freq_cutoff                                 1
    fragment_library_sort_method                                 freq
    fragment_library_trans_origin                                no
    use_internal_energy                                          no
    ligand_atom_file                                             ../../2NNQ_Tutorial/1.dockprep/2nnq_lig_withH.mol2
    limit_max_ligands                                            no
    skip_molecule                                                no
    read_mol_solvation                                           no
    calculate_rmsd                                               no
    use_database_filter                                          no
    orient_ligand                                                no
    bump_filter                                                  no
    score_molecules                                              no
    atom_model                                                   all
    vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dock6/parameters/vdw_AMBER_parm99.defn 
    flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6/parameters/flex.defn
    flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6/parameters/flex_drive.tbl
    ligand_outfile_prefix                                        2NNQ_frag_output
    write_orientations                                           no
    num_scored_conformers                                        1
    rank_ligands                                                 no

The only aspect that is relevant of this fragment library generated is the torsion environment that should be titled 2NNQ.fraglib_torenv.dat Following this step the torsion environments of this molecule will be combined with the file titled full_sorted_fraglib.dat using the python software

    py /gpfs/projects/rizzo/zzz.programs/torsion_env_combination/ 2NNQ.fraglib_torenv.dat /gpfs/projects/rizzo/zzz.programs/dock6.10_2019.06.18/parameters/fraglib_torenv.dat

This should generate a new list of torsion environments titled unique_full_sorted_fraglib.dat

II. Performing a GA using 2NNQ

For this part a new directory will be created in the 2NNQ_GA. This will just be 2NNQ_GA_results. cd into that directory and create a new file titled

    mkdir 2NNQ_GA_results
    cd 2NNQ_GA_results

Following this dock6 will be performed on the molecule

    dock6 -i -o 2NNQ_GA.out

Input the following in order to get the GA working properly. The file will ask for ga_mutations. This will prompt you with addition, deletion, substitution, and replacement mutations and respond yes to all them unless there is a specific purpose to your code to not include these mutation types.

    conformer_search_type                                        genetic
    ga_molecule_file                                             /Path/2nnq_lig_withH.mol2
    ga_fraglib_scaffold_file                                     /gpfs/projects/rizzo/zzz.programs/dock6.10_2019.06.14/parameters    /fraglib_ga_scaffold.mol2
    ga_fraglib_linker_file                                       /gpfs/projects/rizzo/zzz.programs/dock6.10_2019.06.14/parameters   /fraglib_linker.mol2
    ga_fraglib_sidechain_file                                    /gpfs/projects/rizzo/zzz.programs/dock6.10_2019.06.14/parameters/fraglib_sidechain.mol2
    ga_torenv_table                                              ../fraglib/unique_full_sorted_fraglib.dat
    ga_max_generations                                           500
    ga_xover_sampling_method_rand                                yes
    ga_xover_max                                                 150
    ga_bond_tolerance                                            0.5
    ga_angle_cutoff                                              0.14
    ga_check_overlap                                             no
    ga_mutations                                                 yes
    ga_mutate_addition                                           yes
    ga_mutate_deletion                                           yes
    ga_mutate_substitution                                       yes  
    ga_mutate_replacement                                        yes
    ga_mutate_parents                                            yes
    ga_pmut_rate                                                 0.3
    ga_omut_rate                                                 0.7
    ga_max_mut_cycles                                            5
    ga_mut_sampling_method                                       rand
    ga_num_random_picks                                          10
    ga_max_root_size                                             5
    ga_energy_cutoff                                             100
    ga_heur_unmatched_num                                        2
    ga_heur_matched_rmsd                                         2
    ga_constraint_mol_wt                                         550
    ga_constraint_rot_bon                                        10
    ga_constraint_H_accept                                       10
    ga_constraint_H_don                                          5
    ga_constraint_formal_charge                                  4
    ga_ensemble_size                                             200
    ga_selection_method                                          elitism
    ga_elitism_combined                                          no
    ga_elitism_option                                            max
    ga_niching                                                   no
    ga_selection_extinction                                      no
    ga_max_num_gen_with_no_crossover                             1000
    ga_output_prefix                                             2NNQ_GA_output
    use_internal_energy                                          yes
    internal_energy_rep_exp                                      12
    internal_energy_cutoff                                       100
    use_database_filter                                          no
    orient_ligand                                                no
    bump_filter                                                  no
    score_molecules                                              yes
    contact_score_primary                                        no
    grid_score_primary                                           no
    gist_score_primary                                           no
    multigrid_score_primary                                      no
    dock3.5_score_primary                                        no
    continuous_score_primary                                     no
    footprint_similarity_score_primary                           no
    pharmacophore_score_primary                                  no
    hbond_score_primary                                          no
    descriptor_score_primary                                     yes
    descriptor_use_grid_score                                    no
    descriptor_use_multigrid_score                               no
    descriptor_use_continuous_score                              no
    descriptor_use_footprint_similarity                          no
    descriptor_use_pharmacophore_score                           no
    descriptor_use_tanimoto                                      no
    descriptor_use_hungarian                                     no
    descriptor_use_volume_overlap                                no
    descriptor_use_gist                                          no
    minimize_ligand                                              yes
    minimize_anchor                                              yes
    minimize_flexible_growth                                     yes
    use_advanced_simplex_parameters                              no
    simplex_max_cycles                                           1
    simplex_score_converge                                       0.1
    simplex_cycle_converge                                       1
    simplex_trans_step                                           1
    simplex_rot_step                                             0.1
    simplex_tors_step                                            10
    simplex_anchor_max_iterations                                500   
    simplex_grow_max_iterations                                  500
    simplex_grow_tors_premin_iterations                          00
    simplex_random_seed                                          0
    simplex_restraint_min                                        yes
    simplex_coefficient_restraint                                10
    atom_model                                                   all
    vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dock6/parameters    /vdw_AMBER_parm99.defn
    flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6/parameters/flex.defn
    flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6/parameters/flex_drive.tbl