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PostPosted: Mon Jun 29, 2009 4:25 am 
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Hi,

I've been playing around with Vina for a while now, and in general I'm very impressed. I'm particularly interested in using it for flexible docking of small proteins against receptors - around 100-150 rotatable bonds, which gives me a run-time of 50-100 hours on four processors (which is really cool!). The thing is, for many of the interactions I'm interested in, while there are no crystal structures there is plenty of experimental data from alanine mutagenesis and crosslinking studies which could be used to provide constraints in the form of proximity of certain residues. This would, I expect, significantly reduce the sample space (and hence running time) and additionally help to ensure that the resultant structure is close to the real-world situation. Is this something that could be implemented with Vina?

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Tristan Croll
Queensland University of Technology


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PostPosted: Mon Jun 29, 2009 4:42 am 
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Hi,

I've been playing around with Vina for a while now, and I'm really very impressed. I'm particularly interested in using it for docking of small proteins (~100-150 rotatable bonds) to receptors in situations where no crystal structure is (yet) available. In most of my situations, though, there are constraints that could be added from experimental data (crosslinking, mutagenesis etc) which could significantly reduce the sample space (and hence reduce run-time from the current 50-100 hours to something more manageable) and limit solutions to those consistent with experiments. Is this something that could be feasible to implement in Vina?

Thanks,

Tristan Croll
Queensland University of Technology


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PostPosted: Mon Jun 29, 2009 12:01 pm 
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Sorry about the stutter. I missed the statement about moderation the first time around.


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PostPosted: Mon Jun 29, 2009 8:14 pm 
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Tristan,

Vina's intended use is docking of ligands (small molecules), especially in virtual screening for lead discovery.

You may find this discussion useful: http://mgldev.scripps.edu/pipermail/autodock/2009-March/005347.html

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PostPosted: Tue Jun 30, 2009 5:12 am 
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Hi Oleg,

I realise this, but the results I've been getting using it with moderately-sized (20-25-mer) peptides and small proteins whose structures are partially constrained have been at least superficially quite promising. Do you see any fundamental reason why it shouldn't work for these applications, or has it simply not been validated yet?


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PostPosted: Tue Jun 30, 2009 9:59 pm 
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Was the backbone flexible as well?

I wouldn't say that there is a fundamental reason why this must fail. I haven't experimented with trying to use Vina for folding or folding+docking. It'd be surprising to me if this was very successful.

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PostPosted: Wed Jul 01, 2009 1:52 am 
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Perhaps an example would be best. One protein family I'm interested in is the IGF binding proteins (IGFBPs). I've attached an illustration of the N-terminal domain of IGFBP4 below. It's essentially arranged as two "leaves" which are quite tightly constrained by disulfide bonds, with a short linking sequence in between. If I leave the backbone bonds within the disulfide-linked loops fixed (ADT does this by default anyway) this leaves just the sections in green flexible. Allowing all side chains to be flexible as well gives me 131 rotatable bonds; I can reduce this by 20-30 by fixing side chains on the "un-interesting" side of the molecule. Docking this against a potential interactor took somewhere around 60 hours using eight processors, and yielded a couple of quite promising-looking, well-packed complexes.

Attachment:
NBP4.jpg
NBP4.jpg [ 33.47 KiB | Viewed 9168 times ]


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PostPosted: Thu Jul 02, 2009 6:14 pm 
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Tristan,

I'm glad Vina gives you the results you wanted, even if it's somewhat outside its usual application area. However, also check out specialized protein-protein docking programs: many were mentioned in the thread I linked to earlier.

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PostPosted: Tue Jul 07, 2009 7:03 pm 
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I think that the main question remains unawnsered: Is there an easy way to impose constraints in Vina (such a nitrogen-iron distance, for instance)?


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