2021 Denovo tutorial 4 with PDBID 1EFY

Introduction

This tutorial is the second in a series of DOCK tutorials. For part I, please click here. De novo design, in practice, consists of two steps: (1) fragment library generation and (2) de novo construction. DOCK directs ligand assembly in an iterative manner; structures are grown layer by layer as DOCK samples different fragments from the sidechain, linker, and scaffold libraries.

Fragment library generation

Fragments are the basic unit of a molecule (in DOCK, that is). In general, fragments will not contain any rotatable bonds, and are treated as rigid units. The general workflow for fragment library generation proceeds in the following manner: Break the molecule(s) in the input file at each rotatable bond and insert dummy atoms at the point of cleavage. Classify the resulting fragments as sidechains (which have one dummy atom), linkers (which have 2 dummy atoms), or scaffolds (which have three or more dummy atoms).

Directory Setup

Before we begin building our libraries, we should setup our directory structure:

mkdir fraglib dn_focus dn_focus_rescore dn_generic

Focused De Novo Design

Fragment Libraries

In the first part of the tutorial, we will be building a library of fragments out of our original ligand, the benzimidazol inhibitor. Enter the fraglib directory

cd fragllib

Now create a new input file called fraglib.in. This file will be used for generating fragments.

touch fraglib.in

Now interactively run the file in DOCK6:

dock6 -i fraglib.in -o fraglib.out

conformer_search_type                                        flex
write_fragment_libraries                                     yes
fragment_library_prefix                                      fraglib
fragment_library_freq_cutoff                                 1
fragment_library_sort_method                                 freq
fragment_library_trans_origin                                no
use_internal_energy                                          yes
internal_energy_rep_exp                                      12
internal_energy_cutoff                                       100.0
ligand_atom_file                                             1EFY_lig_with_H.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file                                           selected_spheres.sph
max_orientations                                             1000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
bump_filter                                                  no
score_molecules                                              no
atom_model                                                   all
vdw_defn_file                                               
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/vdw_AMBER_parm99.defn
flex_defn_file                                               
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex.defn
flex_drive_file                                              
/gpfs/projects/AMS536/zzz.programs/dock6.9_release/parameters/flex_drive.tbl
ligand_outfile_prefix                                        fraglib.out
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no

The following files should have been generated:

fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, 
fraglib_torenv.dat, fraglib.out_scored.mol2