[Dock-fans] Fwd: discrepancy between rigid and flex

Francesco Pietra chiendarret at gmail.com
Wed May 6 14:55:23 PDT 2009

I am narrowing the problem: fort.10 had no "x", unlike all other
accompanying files. However, there are other problems which I don't
know how to fix:

francesco at tya64:/usr/local/dock6/install/test/chemgrid_generation$
make_phimap $DELPHI_PATH/delphi

  __________DelPhi V. 4 Release 1.1 ______________
 |                                                |
 | A program to solve the PB equation             |
 | in 3D, using non-linear form, incorporating    |
 | many dielectric regions, multisalt ionic       |
 | strength, different probe radii, periodic      |
 | and focussing boundary conditions, utilizing   |
 | stripped optimum successive over-relaxation    |
 | and an improved algorithm for mapping the      |
 | Mol. Surface to the finite-Difference grid     |
 | Recompiled on Linux and PC                     |
 |    January 2002 --------  Walter Rocchia       |
 |__________________           ___________________|
                    DelPhi V. 4

  program started on Wed May  6 2009
              at 23:49:55
 opening parameter file fort.10
PGFIO-F-231/list-directed read/internal file/error on data conversion.
 In source file src/qinttot.f, at line number 1687
0.0u 0.0s 0:00.00 0.0% 0+0k 0+0io 0pf+0w
francesco at tya64:/usr/local/dock6/install/test/chemgrid_generation$

thanks for help


---------- Forwarded message ----------
From: Francesco Pietra <chiendarret at gmail.com>
Date: Wed, May 6, 2009 at 8:52 PM
Subject: Fwd: [Dock-fans] discrepancy between rigid and flex
To: dock-fans <dock-fans at docking.org>

Following my message below, I came across some indications how to set
up the delphi part to the grid.


I do not understand whether, having all required files in the DOCK6.2
installation, that should be run as a tutorial example. What I got:

francesco at tya64:~$ $DOCK_HOME/bin/make_phimap $DELPHI_PATH
cp: cannot stat `vdw.siz': No such file or directory
cp: cannot stat `amb.crg.oxt': No such file or directory
cp: cannot stat `rec+sph.crg': No such file or directory
cat: genric.prm: No such file or directory
/usr/local/delphi-2004-v2: Permission denied.
0.0u 0.0s 0:00.00 0.0% 0+0k 0+0io 0pf+0w
francesco at tya64:~$

In particular, I do not understand the "Permission denied" as I have
rwx rights  about everything in delphi and the software does not
require a license number. It looks like as I misunderstood grossly the

thanks for suggestions

---------- Forwarded message ----------
From: Francesco Pietra <chiendarret at gmail.com>
Date: Tue, May 5, 2009 at 12:32 PM
Subject: Re: [Dock-fans] discrepancy between rigid and flex
To: "John J. Irwin" <jji at cgl.ucsf.edu>

Hi John:

The molecule - this time - is rather small, 15 heavy atoms (C, O, N,
Cl) and 8H. No crystallographic pose, only a variety of molecular
biology and other experiments that converge for a putative binding
site. All those experiments are not for the protein for which X-ray
diffraction crystallographic data are available, though the sequences
are very similar. You may wonder why I got engaged with such a not
straightforward situation: I am interested in the protein and the
clinically used ligand. Clinically used without knowing much, as
evidenced from from I said above.

 In doing the job, I take into account the limitations of the theory I
am using, and therefore I thank you very much for your comments. I'll
stop - under circumstances of the type described - to perform rigid
dock. Perhaps I was intrigued, or mislead, by seeing - in the allHIS
state of the protein, generated manually from the allHIP state - rigid
docking agreeing with the proposed binding site, and flex docking
being into an unreasonable region. Better forget al that and redo,
taking into account what you suggested. To this end, could you please
have a look to the anchor_and_grow.in file that I used, to guess if it
can be improved:

ligand_atom_file   /................AA1_min62.mol2
limit_max_ligands                                            no
skip_molecule                                                no
read_mol_solvation                                           no
calculate_rmsd                                               no
orient_ligand                                                yes
automated_matching                                           yes
receptor_site_file    /......./selected_spheres.sph
max_orientations                                             5000
critical_points                                              no
chemical_matching                                            no
use_ligand_spheres                                           no
flexible_ligand                                              yes
min_anchor_size                                              40
pruning_use_clustering                                       yes
pruning_max_orients                                          100
pruning_clustering_cutoff                                    100
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                                                  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                                2000
simplex_grow_max_iterations                                  2000
simplex_final_min                                            no
simplex_random_seed                                          0
atom_model                                                   all
vdw_defn_file     /usr/local/dock6/parameters/vdw_AMBER_parm99.defn
flex_defn_file      /usr/local/dock6/parameters/flex.defn
flex_drive_file        /usr/local/dock6/parameters/flex_drive.tbl
ligand_outfile_prefix                                        flex
write_orientations                                           no
num_scored_conformers                                        1
rank_ligands                                                 no
One final question. Can electrostatic surface map - such as obtained
from APBS or DelPhi helping to judge visually the likelihood of the
simulated docking? If the suugestion is to use dock3.5 score, is any
recipe how to implement Delphi? (I have an academic - i.e., not
supported - license for Delphi).

Please, take into account that docking occurs within a pore protein,
so that it is the internal electrostatic map (if it can be obtained at
all) which is relevant.


On Tue, May 5, 2009 at 2:19 AM, John J. Irwin <jji at cgl.ucsf.edu> wrote:
> Hi Francesco
> Francesco Pietra wrote:
>> Hi:
>> I wonder whether a large discrepancy between the docking region
>> between rigid and flex dock is a sign of some artifact in setting up
>> the procedures. This implies that i have carefully tried to discover
>> artifacts at no avail.
> The only reason I see for using rigid docking is to investigate whether
> there is a sampling problem with the cognate ligand or possibly a
> problem with scoring.  I see no reason to ever perform rigid docking
> with any ligand other than to redock the crystallographic ligand.  Just
> want that to be clear!
>> For example, with same input files, changing
>> from allHIP state to allHIS state of the protein (and removing the
>> extra  proton of HIS from the pdb file) leads from a normal situation
>> (i.e., rigid and flex differing mainly  in the ligand conformation) to
>> an absurd situation of rigid and flex poses being located nearly as
>> far apart as the range of the protein could allow, while the
>> conformational difference is the same as from the allHIP state of the
>> protein.
> Changing HIS to HIP/HID/HIE (protonating or explicitly deprotonating the
> histidines) should be guided on a case by case basis due to the local
> environment if possible.
>> I understand that without showing the files one can't expect much from
>> such a question, however, i am asking about general experience
>> suggesting what may be grossly wrong under the described observations.
> If you fail to recapitulate the crystallographic ligand pose, the first
> thing to ask yourself is: is this a sampling problem or a scoring
> problem?  You investigate this using a reductionist approach.  e.g.
> score the crystallographic ligand as observed in the crystal structure
> compared to the best docked pose.  Which scores better?  Then, retain
> the top N poses.  Do any of them resemble the crystallographic ligand?
> Break down the score on an atomic basis to get at why the pose you get
> is unexpected. If necessary, break the ligand up into smaller moieties
> and see how they dock.  Conformational sampling is often the culprit in
> molecules with large numbers of rotatable bonds, and fragmenting the
> molecule can help to get at this problem.
>> If one asks what is likely to be the HIS/HIE/HIP state of the protein
>> i can only answer that the complexity is such that pKa-solving
>> programs got confused, proving of no help.
> It is wise to be cautious about automatic pKa prediction programs since
> pKa is very subtle.  Your best bet is to a) look at each site and figure
> out HIE/HID/HIP by hand, if you can.   b) if ambiguous and outside the
> binding site, leave as HIS (or you can create subtle overall charge bias
> if you think that will help) c) if ambiguous and in the binding site,
> you may need to sample both HI[D;E] and HIP explicitly in separate
> docking runs, although you may be able to see that one is clearly
> favored based on available actives.
> Take nothing for granted and set up hypotheses that can fail in
> interesting and informative ways.
> Hope this helps.
> John
>> thanks
>> francesco pietra
>> _______________________________________________
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