2024 DOCK GA tutorial 1 with 1NDV

I. Introduction

A genetic algorithm is a form of de novo design. This form of de novo grows new molecules through a process of evolutionary growth that includes crossover of parent molecules, mutations, and a "natural selection" process. Crossover occurs when two parent molecules have rotatable bonds in the same area of the binding site. This will exchange the fragments between the parents, and creature two new offspring. There are 4 different mutations that can occur during genetic growth. There can be deletion of an existing fragment, addition of a new fragment, substitution of a terminal fragment, and replacement of a linker fragment. After crossover and mutation occurs the new molecules are scored and a select amount are carried over into the next stage of growth. In this tutorial will be using the Elitism elimination method, so only the top scoring molecules will move on to the next generation.

PDB 1NDV

II. Fragment Library Generation for 1NDV

Fragment Libraries

In order for the GA to work, we first need to produce a large and diverse fragment library. Make a directory to run the GA in called "1NDV_GA". Now enter that directory and make a new directory named "fraglib". This is where we will build our fragment library. Create a new file for the fragment library and use it as input for dock6 so we can interactively build the library using the following commands.

touch 1NDV.fraglib
dock6 -i 1NDV.fraglib

Now answer the prompts using the responses below as a guide.

conformer_search_type                                        flex
write_fragment_libraries                                     yes
fragment_library_prefix                                      1ndv.fraglib
fragment_library_freq_cutoff                                 1
fragment_library_sort_method                                 freq
fragment_library_trans_origin                                no
use_internal_energy                                          no
ligand_atom_file                                             /gpfs/projects/AMS536/2024/students/group_2_1NDV/dock_screen/001.structure/1ndv_ligand_only_H_charge.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
use_database_filter                                          no
orient_ligand                                                no
bump_filter                                                  no
score_molecules                                              no
atom_model                                                   all
vdw_defn_file                                                /gpfs/projects/AMS536/zzz.programs/dock6.10/parameters/vdw_AMBER_parm99.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
ligand_outfile_prefix                                        1ndv.frag.output
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no