2021 Denovo tutorial 4 with PDBID 1EFY
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).
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
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
Now create a new input file called fraglib.in. This file will be used for generating fragments.
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