2021 Denovo tutorial 1 with PDBID 1HW9

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Revision as of 15:53, 17 March 2021 by Stonybrook (talk | contribs) (I. Focused De Novo Design)
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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.