Revision as of 07:03, 8 May 2024

Introduction

Continuing from Virtual Screening tutorial, we have the De Novo design tutorial. De Novo means from the beginning, thus, in this tutorial, we are learning to design the molecule that can bind to our protein from scratch. There are 3 different algorithms for the De Novo Design:

1. Generic DeNovo Design
2. Focused Fragment Design
3. DeNovo Refinement

Setting Up Your Environment

Creating new directories in your workspace like the similar:

De Novo Refinement

This algorithm allows us to refine an existing molecule by deleting part of the molecule and let DOCK6 decide what chemical group can be regrow from the deleted area to fit with the protein pocket. Hear is how you can perform it:

Set up your dummy atom

1. Open the protein and ligand in chimera
2. Choose a chemical group inside the binding pocket that you want to delete
3. Get the name of the first atom connecting the chemical group to the rest of the compound by placing the mouse on top of the structure
4. Delete all other atoms after that first atom that you located
5. Save the .mol2 file of the ligand and open it in a text editor program
6. Change the name of the Atom to "DU1" and the atom type to "Du"
7. Save the .mol2 file again

Running De Novo Refinement

Locate to 012 directory and scp the .mol2 file into the directory. Make an input file for DOCK with the following input:

 conformer_search_type                                        denovo
 dn_fraglib_scaffold_file                                     /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_scaffold.mol2
 dn_fraglib_linker_file                                       /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_linker.mol2
 dn_fraglib_sidechain_file                                    /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_sidechain.mol2
 dn_user_specified_anchor                                     yes
 dn_fraglib_anchor_file                                       4s0v_ligand_denovo.mol2
 dn_torenv_table                                              /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/fraglib_torenv.dat
 dn_name_identifier                                           4s0v_denovo
 dn_sampling_method                                           graph
 dn_graph_max_picks                                           30
 dn_graph_breadth                                             3
 dn_graph_depth                                               2
 dn_graph_temperature                                         100.0
 dn_pruning_conformer_score_cutoff                            100.0
 dn_pruning_conformer_score_scaling_factor                    2.0
 dn_pruning_clustering_cutoff                                 100.0
 dn_mol_wt_cutoff_type                                        soft
 dn_upper_constraint_mol_wt                                   1000.0
 dn_lower_constraint_mol_wt                                   0.0
 dn_mol_wt_std_dev                                            35.0
 dn_constraint_rot_bon                                        15
 dn_constraint_formal_charge                                  5
 dn_heur_unmatched_num                                        1
 dn_heur_matched_rmsd                                         2.0
 dn_unique_anchors                                            1
 dn_max_grow_layers                                           1
 dn_max_root_size                                             25 
 dn_max_layer_size                                            25
 dn_max_current_aps                                           5
 dn_max_scaffolds_per_layer                                   1
 dn_write_checkpoints                                         yes
 dn_write_prune_dump                                          no
 dn_write_orients                                             no
 dn_write_growth_trees                                        no
 dn_output_prefix                                             4s0v_denovo_output
 use_internal_energy                                          yes
 internal_energy_rep_exp                                      12
 internal_energy_cutoff                                       100.0
 use_database_filter                                          no
 orient_ligand                                                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                                       ../003.gridbox/grid
 minimize_ligand                                              yes
 minimize_anchor                                              no
 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_grow_max_iterations                                  250
 simplex_grow_tors_premin_iterations                          0
 simplex_random_seed                                          0
 simplex_restraint_min                                        yes
 simplex_coefficient_restraint                                10
 atom_model                                                   all
 vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/vdw_de_novo.defn
 flex_defn_file                                               /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex.defn
 flex_drive_file                                              /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/flex_drive.tbl