[Dock-fans] Re: Re: Missing Scores

Demetri Moustakas moustakas at gmail.com
Fri Apr 8 21:39:10 PDT 2005


I would like to add one note to this thread, and that is that anchor & 
grow will produce no output in the case of a very buried or constrained 
site, in which all possible paths for ligand growth result in bad 
clashes between the ligand and receptor.

DOCK does not have any problem producing conformations for ligands > 7 
rotatable bonds, unless you are docking them into a very constrained 
site.  We do find that for very flexible molecules anchor & grow tends 
to have a lower rate of success at identifying a near-crystal ligand 
pose as the top-scoring pose, because the conformational space to be 
searched is much larger.

If DOCK is failing to produce any output, I would suggest looking at the 
orientations of the anchor that DOCK outputs, to make sure they are 
oriented in a fashion that would allow the remainder of the molecule to 
grow in.

Cheers,
Demetri

> Dear Matthew,
> 
>    If you don't get a response at the end of your run, it is because, for 
> some reason, DOCK did not consider any of the generated poses to have 
> reasonable scores.  We know that it is confusing that nothing is being 
> printed out in the output file and are working to fix that, at which point 
> we will post a bugfix on the web page.
>    For your particular case, because you do have orientations but do not 
> have conformations, you most likely did not get any scored poses because 
> anchor and grow could not find any conformations with reasonable internal 
> energies or reasonable interaction energies.  This generally happens when 
> a) your small molecule has > 7 rotatable bonds or b) your active site is 
> buried or in other ways very sterically restricted.  In order to validate 
> that the problem is actually the flexible ligand sampling, you can perform 
> a rigid dock run (set "flexible_ligand" to no) and see if you get out answers.
>    In order to deal with the sampling issue (if this is indeed the 
> problem), you can either try conformational expansion of your 
> ligand/library prior to docking and then keep your ligands rigid.  You can 
> also try to run either minimizations or md simulations of your 
> receptor-ligand complex to see if you can make your active site less 
> sterically restricted.
>    Please let me know whether this solves your problem.
> 
> Good luck,
> Terry
> 
> 
> At 04:06 PM 4/6/2005, M. A. Lardy [c] wrote:
> 
>>Hi all,
>>
>>I am having difficulty getting the scores out of docking runs.  I am
>>running Dock v5.2.0, and this is what I see from the run:
>>
>>
>>--------------------------------------
>>DOCK v5.2.0-Beta
>>
>>Released March 2005
>>Copyright UCSF
>>Authored by:
>>        Tack Kuntz
>>        Demetri Moustakas
>>        Paula Therese Lang
>>        Scott Pegg
>>--------------------------------------
>>
>>
>>Molecule Library Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>ligand_atom_file
>>23ligands.mol2
>>ligand_outfile_prefix                                        sertanty
>>limit_max_ligands                                            no
>>write_orientations                                           yes
>>write_conformations                                          yes
>>initial_skip                                                 0
>>calculate_rmsd                                               yes
>>use_rmsd_reference_mol
>>23ligands.mol2
>>rank_ligands                                                 yes
>>max_ranked_ligands                                           500
>>scored_mol_output_override                                   no
>>
>>Orient Ligand Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>orient_ligand                                                yes
>>automated_matching                                           yes
>>receptor_site_file
>>/home/lardy/research2/ucn01pocket/1nvqunbound.sph
>>max_orientations                                             1000
>>critical_points                                              no
>>chemical_matching                                            no
>>use_ligand_spheres                                           no
>>
>>Flexible Ligand Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>flexible_ligand                                              yes
>>
>>Anchor & Grow Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>ag_conf_search                                               yes
>>min_anchor_size                                              50
>>num_anchor_poses                                             50
>>number_confs_per_cycle                                       50
>>use_internal_energy                                          yes
>>internal_energy_att_exp                                      6
>>internal_energy_rep_exp                                      12
>>internal_energy_dielectric                                   4.0
>>use_clash_overlap                                            no
>>
>>Bump Filter Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>bump_filter                                                  yes
>>bump_grid_prefix                                             grid
>>max_bumps                                                    2
>>
>>Master Score Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>score_molecules                                              yes
>>
>>Energy Score Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>energy_score_primary                                         yes
>>energy_score_secondary                                       yes
>>vdw_scale                                                    1
>>es_scale                                                     1
>>nrg_grid_prefix                                              grid
>>
>>Simplex Minimization Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>minimize_ligand                                              yes
>>minimize_anchor                                              yes
>>minimize_flexible_growth                                     yes
>>minimize_final_pose                                          yes
>>use_advanced_simplex_parameters                              yes
>>simplex_anchor_min_max_iterations                            50
>>simplex_anchor_min_max_cycles                                1
>>simplex_anchor_min_score_converge                            0.1
>>simplex_anchor_min_cycle_converge                            1.0
>>simplex_anchor_min_trans_step                                1.0
>>simplex_anchor_min_rot_step                                  0.1
>>simplex_anchor_min_tors_step                                 10.0
>>simplex_flex_min_max_iterations                              10
>>simplex_flex_min_max_cycles                                  1
>>simplex_flex_min_score_converge                              0.1
>>simplex_flex_min_cycle_converge                              1.0
>>simplex_flex_min_trans_step                                  1.0
>>simplex_flex_min_rot_step                                    0.1
>>simplex_flex_min_tors_step                                   10.0
>>simplex_final_min_max_iterations                             100
>>simplex_final_min_max_cycles                                 1
>>simplex_final_min_score_converge                             0.1
>>simplex_final_min_cycle_converge                             1.0
>>simplex_final_min_trans_step                                 1.0
>>simplex_final_min_rot_step                                   0.1
>>simplex_final_min_tors_step                                  10.0
>>simplex_random_seed                                          0
>>
>>Atom Typing Parameters
>>------------------------------------------------------------------------ 
>>------------------
>>atom_model                                                   all
>>vdw_defn_file
>>/usr/local/software/dock/dock.5.2_linux/parameters/ vdw_AMBER_parm94.defn
>>flex_defn_file
>>/usr/local/software/dock/dock.5.2_linux/parameters/flex.defn
>>flex_drive_file
>>/usr/local/software/dock/dock.5.2_linux/parameters/flex_drive.tbl
>>chem_defn_file
>>/usr/local/software/dock/dock.5.2_linux/parameters/chem.defn
>>------------------------------------------------------------------------ 
>>------------------
>>
>>Initializing Library File Routines...
>>Initializing Orienting Routines...
>>Initializing Conformer Generator Routines...
>>Initializing Bump Filter Routines...
>> Reading the bump grid from grid.bmp
>>Initializing Energy Score Routines...
>> Reading the energy grid from grid.nrg
>>
>>
>>23 Molecules Processed
>>Elapsed time:   56.82 seconds
>>
>>It appears to me that the run was successful, but when I open the
>>sertanty prefix files, they are all empty with one exception.  The
>>exception being that the sertanty_orient.mol2 has structures.  Am I
>>missing something?  I am more than happy to share any other information
>>that might be relevant to this problem.
>>
>>Thanks,
>>Matthew
>>
>>
>>--
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> 
> 
> ***NOTE:  This is a new e-mail address (terry at cgl.ucsf.edu)  Please update 
> your address book!***
> 
> P. Therese (Downing) Lang
> Kuntz and James Labs
> UCSF - CCB Graduate Program
> Phone:  (415)476-3986
> 
> 
> 
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