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PostPosted: Mon Jan 25, 2010 11:25 pm 
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I'm a new user of Autodock vina and I'm trying to dock potential substrates into the active site of the enzyme I'm interested in. However this substrate will make a covalent Schiff base adduct with the enzyme and I'm worried that simply trying to dock the substrate into the enzyme will produce an invalid solution as the substrate and the active site lysine residue will have to get too close (as they form the covalent bond). Is this a problem and if so is there a way around it?

I did wonder if I could simply fix one atom in the substrate into the correct position for the covalent bond and then simply let the rest of the substrate search out the best binding position, but I cannot find if/how this would be possible in Vina.

Any help would be useful.

Alan


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PostPosted: Tue Feb 02, 2010 1:41 am 
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I would like to know the same thing. From my understanding you need to define the ligand as a flexible residue and dock that in, but there are a few points I don't understand:

1.) How do I make the residue the ligand is bound to flexible as well? I was thinking that I could define a new, nonstandard residue that would be both the ligand and the amino acid it binds to, but when I use the "prepare_flexibleresidue" script on that and specify that residue it gives me an empty flexible.pdbqt file

2.) Does VINA require a ligand file? If I am "docking" the flexible part into the rigid one I don't have a ligand (since it's defined in the flexible pdbqt).

Any advice would be appreciated!


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PostPosted: Tue Feb 02, 2010 10:11 pm 
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I think people do the so-called covalent docking with AutoDock4 by treating the ligand as a side-chain and supplying an insignificant ligand, like a water molecule. You could try the same thing with Vina (ligands with 0 atoms should be acceptable).

However, one should keep in mind that Vina predicts intermolecular affinities by design. So, even if the predicted binding mode provides useful information, the predicted affinity should be 0, as there is only one molecule.

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PostPosted: Fri Mar 04, 2011 4:00 pm 
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I'm a newbee to Autodock and I am trying my hand on 'covalent docking' in Vina. Up to now, I've been using the 'flexible sidechain' method - creating an inhibitor as a sidechain to my amino acid of interest, then docking a watermolecule in a grid somewhere in the protein, while defining the inhibitor/sidechain as a flexible residue.

I would also like to use the 'grid-based' approach as described by Garrett Morris in J. Comp. Sci 2009, 30:2785-91, where they fix 1 or 2 atoms. Is this possible with Vina, since in Vina the gridmaps are automatically generated? If so, how would I proceed? How can I create the Gaussian function with zero energy at the side of attachment(s)? (I actually would like to fix a molecule to a protein in 2 sites, creating a sort of cross-link). Any input is very much appreciated.


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PostPosted: Fri Mar 11, 2011 2:54 pm 
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I'm trying to use Vina for covalent docking.

In my experience, contrary to what was suggested by Oleg's message, an empty ligand file is not acceptable, since I get an error message saying that the ligand has 0 atoms, and the program stops. Am I doing something wrong?

In any case, I tried to include a water molecule as an "insignificant ligand". In this case I do get a binding energy. Is it relevant, or is it just the binding energy of the water molecule?

Some more general questions:
1) if the energy of the flexible sidechain with the covalent complex is not included in the computation, how is the best docked structure selected?
2) the water molecule used as the ligand in the end is docked in the active site. Doesn't it perturb the conformation of the docked flexible sidechain?
3) since I am interested in the "intramolecular" energy of the covalent ligand, could I use Vina to find the best docked pose, and then use autodock to caluclate the energy? How would this be done?

Any help would be highly appreciated!

Lorenzo Stella


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stella@stc.uniroma2.it


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PostPosted: Fri Mar 11, 2011 11:06 pm 
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lorenzo.stella wrote:
In my experience, contrary to what was suggested by Oleg's message, an empty ligand file is not acceptable, since I get an error message saying that the ligand has 0 atoms, and the program stops. Am I doing something wrong?


No, you are right. 0 atoms won't work.

You could use a single HD atom instead of a water, exploiting the fact that Vina uses a united-atom scoring function:
Code:
ROOT
ATOM      1  H   ZMR d1001     -27.254  15.059 -21.209  0.00  0.00     0.206 HD
ENDROOT
TORSDOF 0


The output you'd get (with side chains) might look like this:
Code:
mode |   affinity | dist from best mode
     | (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
   1          0.0      0.000      0.000
   2          0.1      2.755      3.285
   3          0.5      1.326      1.821
   4          1.0      1.794      2.315
   5          1.0      1.826      2.398
   6          1.2      1.313      1.871
   7          1.6      1.773      2.681
   8          1.8      2.028      3.166
   9          2.5      1.710      2.184

As expected, the "intermolecular energy" is 0. The other (2+) modes have positive energies, which are due to the less favorable side-chain positions.

I don't know if you could still feed Vina's output into AutoDock 4, and score it there (If you can, you are really exploiting a bug/misfeature in AutoDock 4 - the free energy of binding water, or another small molecule, is supposed to be near 0), but you could try.

You could also try separating the "side chain", and then scoring it as a ligand with
Code:
vina --score_only ...

This is probably better, since the scoring function will be the same as the one used for minimization.

Oleg

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PostPosted: Sat Mar 12, 2011 12:36 am 
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... Note that if you do this naively, the score will probably be dominated by the clashes of the ligand atom that you think is covalently binding to the receptor.

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PostPosted: Mon Mar 14, 2011 12:54 pm 
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OK. I tried with the H atom, but I do not get a 0 binding energy! According to what Oleg wrote, I cannot understand why this is so. Am I doing something wrong? This is my output:

Output will be H_out.pdbqt
Reading input ... done.
Setting up the scoring function ... done.
Analyzing the binding site ... done.
Using random seed: 909054496
Performing search ... done.
Refining results ... done.

mode | affinity | dist from best mode
| (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
1 -4.6 0.000 0.000
2 -4.1 1.632 1.903
3 -3.9 1.483 5.243
4 -3.3 2.215 5.188
5 -3.3 2.825 5.947
6 -3.2 3.146 5.430
7 -3.2 3.044 6.230
8 -2.9 3.186 5.097
9 -2.9 1.602 5.528

I am attaching the input files (conf.txt; 1K3L..._RIGID.pdbqt is the rigid receptor, 1K3L..._FLEX.pdbqt is the flexible side chain, H.pdbqt is the "ligand") and the output file H_out.pdbqt

Best,
Lorenzo


Attachments:
Vina_files.zip [97.38 KiB]
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PostPosted: Mon Mar 14, 2011 5:07 pm 
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I'm by no means an expert, but aren't those negative energies there, because those represent more favorable sidechain positions (as opposed to Oleg's example, where the positive energies were due to less favorable sidechain positions)?


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PostPosted: Mon Mar 14, 2011 11:22 pm 
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lorenzo.stella wrote:
OK. I tried with the H atom, but I do not get a 0 binding energy!


Lorenzo,

It's not immediately obvious to me why you would not get a 0. I'm attaching my test files, in case you want to use them as an example of flexible side chains. If you start to gradually change my files to be more like yours, and at some point, the answer stops being 0, you might figure out the nature of the problem (in which case, do let me know what it was, if you think it might be a bug).

Oleg

Code:
$ time vina --config conf.txt
#################################################################
# If you used AutoDock Vina in your work, please cite:          #
#                                                               #
# O. Trott, A. J. Olson,                                        #
# AutoDock Vina: improving the speed and accuracy of docking    #
# with a new scoring function, efficient optimization and       #
# multithreading, Journal of Computational Chemistry 31 (2010)  #
# 455-461                                                       #
#                                                               #
# DOI 10.1002/jcc.21334                                         #
#                                                               #
# Please see http://vina.scripps.edu for more information.      #
#################################################################

Output will be ligand_out.pdbqt
Detected 2 CPUs
Reading input ... done. 
Setting up the scoring function ... done.
Analyzing the binding site ... done.
Using random seed: -462172146
Performing search ...
0%   10   20   30   40   50   60   70   80   90   100%
|----|----|----|----|----|----|----|----|----|----|
***************************************************
done.
Refining results ... done.

mode |   affinity | dist from best mode
     | (kcal/mol) | rmsd l.b.| rmsd u.b.
-----+------------+----------+----------
   1          0.0      0.000      0.000
   2          0.1      2.755      3.285
   3          0.4      1.336      1.634
   4          0.4      1.320      1.808
   5          0.9      1.787      2.415
   6          1.1      2.942      3.925
   7          1.7      1.727      2.722
   8          1.9      2.058      3.274
   9          2.6      1.933      2.656
Writing output ... done.

real    5m55.301s
user    11m29.775s
sys     0m1.494s


Results screenshot (input is green) :

Attachment:
HD_ligand.png
HD_ligand.png [ 335.33 KiB | Viewed 17241 times ]


Attachments:
HD_ligand.zip [83.54 KiB]
Downloaded 611 times

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