[Dock-fans] Docking Large Flexible Molecules

Fuhrman, Kit kit.fuhrman at pathology.ufl.edu
Thu Jul 1 10:39:11 PDT 2010


Hi Trent,
Thanks for the help and pointing me in the right direction.  I read the first part of that paragraph before, but somehow missed the second.  Too much coffee.  I was a little nervous to use the unfiltered sphere set, because the filter selects for only one sphere per atom.  I wasn't sure of the purpose for the one-sphere-per-atom rule and didn't want to inadvertently break the algorithm.  But on further thought, I guess it's just done that way to reduce the complexity of the search (feel free to correct me if I'm wrong on that) .

I'll give cluster 0 a try and see how it goes.

Best,
Kit


On Jun 30, 2010, at 5:06 PM, Trent E. Balius wrote:

Hi Kit,

Yes, I believe that cluster 0 are the spheres that you should be using for blind docking.

See the following section:
http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm#SphgenOutput

Quoting this section:
"The clusters are listed in numerical order from largest cluster found to the smallest. At the end of the clusters is cluster number 0. This is not an actual sphere cluster, but a list of allof the spheres generated whose radii were larger than the minimum radius, before the filtering heuristics ( i.e., allowing only one sphere per atom and using a maximum radius cutoff) and clustering were performed. Cluster 0 may be useful as a starting point for users who want to explore a wider range of possible clusters than is provided by the standard sphgen clustering routine."

I hope this helps,

Trent E. Balius
Graduate Student, Rizzo Group,
Department of Applied Mathematics and Statistics,
Stony Brook University.
Office: Math Tower 3-129, Phone: (631) 632-8519
URL: http://www.ams.sunysb.edu/~tbalius/


-----Original Message-----
From: Fuhrman, Kit <kit.fuhrman at pathology.ufl.edu>
To: dock-fans at mailman.docking.org <dock-fans at mailman.docking.org>
Cc: Trent E. Balius <tbalius at aol.com>
Sent: Thu, Jun 24, 2010 1:41 pm
Subject: Re: [Dock-fans] Docking Large Flexible Molecules

Hi Trent
Thank  you for your insight.

I tried a few pruning_conformer_score_cutoff settings.  Setting it at 1000 resulted in reasonable docked conformations.  The results showed reasonable hydrogen bonding between the molecule and the target protein.  I tried docking the same compound to a different pdb (same protein), and the program started failing again.  I then lowered the max_orientation to 5000 and it started working again.

After reading the manual a little more carefully, I was a bit unsure if I was setting up the spheres correctly.  I basically use all the spheres that are in the cluster.sph file excluding the spheres that are only in cluster 0 and not in any other cluster.    Is this the what you would suggest for a blind docking?  Or should I be using all the spheres?
Best,
Kit





On Jun 20, 2010, at 8:43 PM, Trent E. Balius wrote:


Hi Kit,

You may need to increase the "pruning_conformer_score_cutoff" parameter.

Try:
pruning_conformer_score_cutoff     1000

The pruning compares the Intermolecular interactions to the cutoff.  Now, it also sees if the internal energy exceeds the cutoff as well.

see the following two links for more info:

http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm#PruningtheConformationSearchTree
http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm#InternalEnergyCalculation


In addition you should consider using the verbose flag and looking at the growth statistics which will give you insight into what is going wrong.

dock6 -i dock.in -o dock.out -v

see the following for more info:

http://dock.compbio.ucsf.edu/DOCK_6/dock6_manual.htm#GrowthTreeAndStatistics


Good luck and I hope that this helps,

Trent E. Balius
Graduate Student, Rizzo Group,
Department of Applied Mathematics and Statistics,
Stony Brook University.
Office: Math Tower 3-129, Phone: (631) 632-8519
URL: http://www.ams.sunysb.edu/~tbalius/<http://www.ams.sunysb.edu/%7Etbalius/>


-----Original Message-----
From: Fuhrman, Kit <kit.fuhrman at pathology.ufl.edu<mailto:kit.fuhrman at pathology.ufl.edu>>
To: dock-fans at mailman.docking.org<mailto:dock-fans at mailman.docking.org> <dock-fans at mailman.docking.org<mailto:dock-fans at mailman.docking.org>>
Sent: Sun, Jun 20, 2010 2:47 pm
Subject: [Dock-fans] Docking Large Flexible Molecules


Dear dockfans,

















I'm trying to dock a molecule with a molecular weight of 536.57 and 12 rotatable








bonds to a globular  protein of  247 amino acids .  I know this is a little








outside dock's validated range, but I'm trying to get a feel for where the








molecule is binding.  I've tried a number of parameters and I often get  the








infamous error:

















ERROR:  Could not complete growth.








        Confirm that the grid box is large enough to contain the ligand,








        and try increasing max_orientations.

















Since I'm not sure of the active site, I'm docking over the whole protein with a








6 angstrom margin.

















I've tried different max_orientations values at  1000, 5000, and 10000.  I








actually get the error more often at higher max_orientation values.

















I've also tweaked these parameters to see if that would help.








max_orientations = [500,1000,5000,10000]








pruning_max_orients = [500, 1000,2500]








pruning_clustering_cutoff  = [100, 250, 500]

















Are these the right parameters to change?  Should I go higher?  Some of the








results I get suggest that I should increase pruning_clustering_cutoff along








with pruning_max_orients.  Is that a reasonable conclusion?

















I'm only docking one molecule, so I'm not too worried about computational time.








I'm using a grid score with dock6.4.

















Any insight would be helpful.








Best regards,

















Kit Fuhrman








Department of Pathology, Immunology and Laboratory Medicine








University of Florida College of Medicine








kit.fuhrman at pathology.ufl.edu












































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Dock-fans at mailman.docking.org








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Kit Fuhrman
IDP Graduate Student
Department of Pathology, Immunology and Laboratory Medicine
University of Florida College of Medicine
kit.fuhrman at pathology.ufl.edu<mailto:kit.fuhrman at pathology.ufl.edu>




=

Kit Fuhrman
IDP Graduate Student
Department of Pathology, Immunology and Laboratory Medicine
University of Florida College of Medicine
kit.fuhrman at pathology.ufl.edu<mailto:kit.fuhrman at pathology.ufl.edu>




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