2021 Denovo tutorial 1 with PDBID 1HW9
In this session, we are going to use the predetermined structures from the virtual screen tutorial to do de novo design
I. Focused De Novo Design
In the focused De Novo Design, we will generate the same ligand present in the structure by connecting fragments from scratch. Putting the generated fragments back into the pocket, we could check how our simulation works in terms of the protein we are interested in
Fragment Libraries
First, a focused fragment library will be generated based on the original ligand. The fragments would build the same ligand in an atomic structure.
Create a new directory for the fragment library, use the command:
mkdir 010_dn_fraglib
Create a new input file for fragment generation, use the command:
touch fragment.in
Use the following parameters to answer default questions from the dock program:
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 ../001.structure/1HW9_ligand_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 ../002.surface_spheres/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 fragment.out write_orientations no num_scored_conformers 1 rank_ligands no
Once the fragment.in the file is generated, run the dock6 program using the fragment.in as the input file:
dock6 -i fragment.in -o fragment.out
After the fragment library generation is complete, 6 files would be generated (fraglib_linker.mol2, fraglib_rigid.mol2, fraglib_scaffold.mol2, fraglib_sidechain.mol2, and fraglib_torenv.dat)
Using the grew command, we can check the number of fragments generated. Scp the mol2 files and open the files in Viewdock using Chimera can see how they match with the original structure file.
grep -wc MOLECULE *.mol2 | wc -l
Focused Denovo Growth
The de novo dock would be run by using fragments generated from the library. The fragments would connect with each other fragments with some constraints such as charge and molecular weight. DOCK program would make the fragments connection in an appropriate way before adding other single fragment.
