2012 DOCK tutorial with Streptavidin

For additional Rizzo Lab tutorials see DOCK Tutorials.

I. Introduction

DOCK

DOCK was developed by Irwin D. "Tack" Kuntz, Jr., PhD and colleagues at UCSF. Please see the webpage at UCSF DOCK.

DOCK is a molecular docking program used in drug discovery. This program, given a protein active site and a small molecule, tries to predict the correct binding mode of the small molecule in the active site, and the associated binding energy. Small molecules with highly favorable binding energies could be new drug leads. This makes DOCK a valuable drug discovery tool. DOCK is typically used to screen massive libraries of millions of compounds against a protein to isolate potential drug leads. These leads are then further studied, and could eventually result in a new, marketable drug. DOCK is works well as a screening procedure for generating leads, but not nearly as well for optimization of those leads. Original DOCK used only rigid body docking, DOCK 4.0, however, introduced flexible ligand docking by either a)incremental construction or b)random search.

Incremental construction (aka anchor and grow) could be roughly described by a three step process: 1) rigid portion of ligand (anchor) is docked by geometrical methods 2) non-rigid segments added; energy minimized 3) the resulting configurations are 'pruned' and energy re-minimized, yielding the docked configurations

Random search method involves docking random conformations of ligand as independent rigid objects. The number of conformations allowed per rotatable bond is arbitrary and user controlled. The receptor is always held rigid in DOCK 4.0.

Streptavidin & Biotin

Streptavidin is a tetrameric prokaryoke protein that binds the co-enzyme biotin with an extremely high affinity. The streptavidin monomer is composed of eight antiparallel beta-strands which folds to give a beta barrel tertiary structure. A biotin binding-site is located at one end of each β-barrel, which has a high affinity as well as a high avidity for biotin. Four identical streptavidin monomers associate to give streptavidin’s tetrameric quaternary structure. The biotin binding-site in each barrel consists of residues from the interior of the barrel, together with a conserved Trp120 from neighbouring subunit. In this way, each subunit contributes to the binding site on the neighboring subunit, and so the tetramer can also be considered a dimer of functional dimers.

Biotin is a water soluble B-vitamin complex which is composed of an ureido (tetrahydroimidizalone) ring fused with a tetrahydrothiophene ring. It is a co-enzyme that is required in the metabolism of fatty acids and leucine. It is also involved in gluconeogenisis.

Organizing Directories

While performing docking, it is convenient to

VI. Virtual Screening

Virtual Screening Protocol

Sample flex virtual screening input file

ligand_atom_file                       3_t60.mol2
limit_max_ligands                      no
skip_molecule                          no
read_mol_solvation                     no
calculate_rmsd                         no
use_database_filter                    yes
dbfilter_max_heavy_atoms               999
dbfilter_min_heavy_atoms               0
dbfilter_max_rot_bonds                 999
dbfilter_min_rot_bonds                 0
dbfilter_max_molwt                     9999.0
dbfilter_min_molwt                     0.0
dbfilter_max_formal_charge             10.0
dbfilter_min_formal_charge             -10.0
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
use_internal_energy                    yes
internal_energy_rep_exp                12
flexible_ligand                        yes
min_anchor_size                        5
pruning_use_clustering                 yes
pruning_max_orients                    100
pruning_clustering_cutoff              100
pruning_conformer_score_cutoff         25.0
use_clash_overlap                      no
write_growth_tree                      no
bump_filter                            no
score_molecules                        yes
contact_score_primary                  no
contact_score_secondary                no
grid_score_primary                     yes
grid_score_secondary                   no
grid_score_rep_rad_scale               1
grid_score_vdw_scale                   1
grid_score_es_scale                    1 
grid_score_grid_prefix                 grid
dock3.5_score_secondary                no
continuous_score_secondary             no
gbsa_zou_score_secondary               no
gbsa_hawkins_score_secondary           no
amber_score_secondary                  no
minimize_ligand                        yes
minimize_anchor                        yes
minimize_flexible_growth               yes
use_advanced_simplex_parameters        no
simplex_max_cycles                     1
simplex_score_converge                 0.1
simplex_cycle_converge                 1.0
simplex_trans_step                     1.0
simplex_rot_step                       0.1
simplex_tors_step                      10.0
simplex_anchor_max_iterations          1000
simplex_grow_max_iterations            20
simplex_grow_tors_premin_iterations    0
simplex_random_seed                    0
simplex_restraint_min                  no
atom_model                             all
vdw_defn_file                          vdw.defn
flex_defn_file                         flex.defn
flex_drive_file                        flex_drive.tbl
ligand_outfile_prefix                  vs
write_orientations                     no
num_scored_conformers                  1
rank_ligands                           yes
max_ranked_ligands                     20000

VII. Running DOCK in Serial and in Parallel on Seawulf

Use PBS Queue as a reference.