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PostPosted: Thu Jun 25, 2009 9:00 pm 
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I'm new to docking, so I assume I'm doing something wrong. I have a crystal structure with a small, bound ligand. Using vina, I docked the flexible ligand to the rigid protein. The binding site from the crystal structure was ranked second (both the 1st and 2nd binding modes had binding affinities of -5.3 kcal/mol.)

The ligand has 3 active torsions. I decided to make the residues around the binding site flexible: there are 11 residues that form the pocket, resulting in 25 additional torsions. I reran vina, and while it also finds the correct binding mode, the binding affinity is weaker. I was, perhaps, naively, expecting the binding to be lower in free energy, as allowing the pocket to be flexible might allow for stronger binding. In general, should allowing flexible residues in the pocket result in stronger binding, relative to the rigid structure?

I reran vina a number of times and tried a range of exhaustiveness from 8 to 25. If I do this with the RIGID protein, the binding affinity is the same, regardless of the exhaustiveness parameter (in the range 8-25). When I do this with flexible residues around the pocket, I get the following for the best binding affinities:

exhaustiveness= 8: 1 -4.8 0.000 0.000
exhaustiveness=10: 1 -3.0 0.000 0.000
exhaustiveness=11: 1 -3.2 0.000 0.000
exhaustiveness=15: 1 -2.9 0.000 0.000
exhaustiveness=16: 1 -6.5 0.000 0.000
exhaustiveness=17: 1 -6.6 0.000 0.000
exhaustiveness=18: 1 -3.5 0.000 0.000
exhaustiveness=20: 1 -4.7 0.000 0.000
exhaustiveness=25: 1 -3.1 0.000 0.000

Is this to be expected? Or is this due to the fact that I have a total of 28 torsions? Or perhaps something else.

I was hoping to use vina to estimate the relative binding affinity of a number of ligands in this site, relative to the same site in a different structure (that is constructed by homology modeling).

Note also, the physical size of the search space is rather large: The protein has over 300 residues and the box is is about 80 x 60 x 100 Angstroms^3.


PostPosted: Fri Jun 26, 2009 12:16 am 
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Joined: Mon Oct 20, 2008 9:39 pm
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In general, should allowing flexible residues in the pocket result in stronger binding, relative to the rigid structure?

No. Imagine, for example, that your rigid residues are somewhat "clashed" with each other. "Releasing" them might crowd the ligand more or otherwise make the intermolecular part of the estimated interaction worse.

I suggest reading the paper, especially its "intro" and "optimization" parts.

The meaning of "exhaustiveness" is explained in the manual. It affects the results, although somewhat indirectly.

If you don't get your question answered here, consider posting it on the AutoDock mailing list instead of this forum. Please do not email or PM me with requests for help.

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