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PostPosted: Mon Jun 22, 2009 3:20 pm 
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Hello Vina Users!

I have been using AutoDock4.0 on OSX for the virtual screening of carbohydrate-processing enzymes, and recently ventured into testing Vina. I am experiencing some trouble replicating my AutoDock results, however.

For example, I used Vina to dock the small molecule swainsonine to alpha-mannosidase (complex 1hww in the PDB), but not with great success. None of the binding modes output by Vina matched the orientation of swainsonine in the original crystal structure (although the modes were in the same location within the active site). A rigid docking (no flexible residues) of swainsonine using AutoDock 4.0, however, produced a lowest energy cluster that did match the crystal structure. There is a zinc atom at the bottom of the active site, to which I assigned a +1 charge. Could this be having an effect on the results? The input file I used for Vina is reproduced below.

receptor = 1hww.pdbqt
ligand = in7_srrr.pdbqt

center_x = 30.989
center_y = 65.508
center_z = 8.221

size_x = 20
size_y = 20
size_z = 20

For a second test, I used Vina to dock phosphocholine to McPC-603 (PDB ID 2mcp), one of the test complexes used in the AutoDock paper:

Morris, G. M., Goodsell, D. S., Halliday, R.S., Huey, R., Hart, W. E., Belew, R. K., Olson, A. J., J. Computational Chemistry, 1998, 19, 1639-1662.

Once again, whereas a rigid docking with AutoDock4.0 was able to mimic the crystal structure, the Vina docking was not. The Vina binding modes actually flipped phosphocholine 180 degrees in the active site, to the effect that the trimethyl amino and phosphate groups were oriented oppositely as compared to the PDB structure and AutoDock results. The Vina input is given below:

receptor = 2MCP.pdbqt
ligand = phosphocholine.pdbqt

center_x = 52
center_y = 60
center_z = -34

size_x = 20
size_y = 20
size_z = 20

Could some issue with charges be responsible for these results, or is there something I am missing? If anyone could offer some insight, I would be very appreciative. Thanks in advance!

Mary Barden

Department of Chemistry and Biochemistry
Providence College
Providence, R.I.


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PostPosted: Mon Jun 22, 2009 9:15 pm 
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Mary,

Quote:
Could some issue with charges be responsible for these results

No. This is mentioned in the manual, and the paper discusses the scoring function as well. Vina ignores the user's charge assignments.

Quote:
Code:
receptor = 2MCP.pdbqt
ligand = phosphocholine.pdbqt

center_x = 52
center_y = 60
center_z = -34

size_x = 20
size_y = 20
size_z = 20



It looks like, in your second case at least, the search space is off (see attached screenshot).

Quote:
or is there something I am missing?


I don't know if you are doing something incorrectly besides the above (you didn't even attach your PDBQT files), but in general, the correct binding mode can not be guaranteed. AutoDock Vina simply gives you much better odds than AutoDock 4.0, especially for large ligands. You can however find cases when AD4 is correct and Vina is not (I didn't try repeating your experiment to see if this is one of them). Please see our paper for the statistical comparison on a large and diverse set.


Attachments:
2mcp.png
2mcp.png [ 207.43 KiB | Viewed 46568 times ]

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PostPosted: Tue Jul 07, 2009 7:07 pm 
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From our experience: I think Vina has issues with OH---OH hydrogen bonds, which may explain why it is not able to predict the correct pose for your ligands.

Sorry, but I did not have the time to submit a bug report yet.


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PostPosted: Tue Jul 07, 2009 9:31 pm 
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mirix wrote:
From our experience: I think Vina has issues with OH---OH hydrogen bonds, which may explain why it is not able to predict the correct pose for your ligands.


Edelmiro,

You raised this before:
http://mgldev.scripps.edu/pipermail/autodock/2009-June/thread.html#5938

Here are the answers:
http://mgldev.scripps.edu/pipermail/autodock/2009-June/005939.html
http://mgldev.scripps.edu/pipermail/autodock/2009-June/005944.html

mirix wrote:
Sorry, but I did not have the time to submit a bug report yet.

We'll wait.

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PostPosted: Wed Jul 08, 2009 11:02 am 
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Well, at the beginning we though the problem was just directionality, but obviously this is not the case, as explained by Mark. The problem is that C=O---H-O is always recognised, but O-H---OH is not, even when docking otherwise identical ligands (empirically, both should be similarly efficient).


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PostPosted: Wed Jul 08, 2009 5:39 pm 
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Quote:
Well, at the beginning we though the problem was just directionality, but obviously this is not the case, as explained by Mark


Dear Edelmiro Moman,

I think you are misreading what Mark and I wrote. If your RMSD from the experimental structure is very good, as you yourself admitted, there is no reason to think there is a problem.

Because I care very much about the quality of my software, I go out of my way to investigate bug reports from users, even when everything seems to say it's not a bug (as in your case), but if you couldn't be bothered to submit a reproducible case all this time, you have no basis to be complaining.

If you would be happier using any other docking program, perhaps that's what you should do?

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