ADL: Vina: docking results dependent on ligand input conformation?

Brian Moldover moldoverb at gmail.com
Tue Apr 15 08:42:44 PDT 2014


Also my experience. If you're setting up a high-throughput screen against a
known -liganded target, the best approach would be to use the original
conformation and ensure you're binding properly. Then you know you have the
binding site correct. 

-----Original Message-----
From: autodock-bounces at scripps.edu [mailto:autodock-bounces at scripps.edu] On
Behalf Of Soren Wacker
Sent: Tuesday, April 15, 2014 11:37 AM
To: autodock at scripps.edu
Subject: Re: ADL: Vina: docking results dependent on ligand input
conformation?

Hi.

IMO, including the proper conformers and let them rigid would be the better
way to go.
Since, then all solutions are somehow realistic. However, if you let them
rotate you have just a few "realistic" solutions and a lot of trash. 

Soren

________________________________________
From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on behalf
of Oleg Trott [trott at scripps.edu]
Sent: Monday, April 14, 2014 9:27 PM
To: autodock at scripps.edu
Subject: Re: ADL: Vina: docking results dependent on ligand input
conformation?

Hi

If there are two low-energy basins separated by a high-energy barrier,
AD4 and Vina should sample both basins, given enough time/exhaustiveness,
not unlike the fact that a coin toss should give you "tails" given enough
samples.

Furthermore, for Vina, as a consequence of its property of being unbiased,
the probability of finding your results in one or the other basin should not
depend on the input conformation (i.e. the values of the ROTATABLE torsion
angles, position and orientation in the input structure). I'm not sure the
same holds for AD4 -- at least in the past it didn't.

The issue you bring up is a separate one: in Vina and AD4, torsions are
either totally rigid, or freely rotatable (unfortunately), so it's not an
issue of Vina staying in a certain basin because of a barrier, but of the
existence of the other basin, as far as the docking program is concerned.

So, if you want to model a molecule where a torsion is expected to only take
values near, say, 0 or 180 degrees, you would probably need to dock the two
conformations (with the torsion "frozen") separately, as you suggest.
Another approach is to let such torsions be rotatable, but filter out the
implausible results in, say, a virtual screen.

Oleg




On Mon, Apr 14, 2014 at 5:00 PM, Soren Wacker <swacker at ucalgary.ca> wrote:
> However, what if there are different conformers that are separated by a
big energy barrier? Autodock and Vina will stay in a local minimum and not
sample the full conformation space, right? E.g. Cis- and trans conformations
in 1,3-dimethyl-urea. This actually happens because amide bonds are
considered rigid by default. In such cases it makes totally sense to perform
the docking with the different conformations and the output will depend on
the particular conformation of the input molecule. At least, if the
conformers have similar chemical stability.
>
> Would you agree?
>
>
> --
> Dr. Soeren Wacker
> Centre For Molecular Simulation, BI # 547 The University of Calgary
> 2500 University Drive (NW)
> Calgary, Alberta
> Canada, T2N 1N4
>
> Tel.:   ++1 (403) 210 7860
> Email:  swacker at ucalgary.ca
>
> ________________________________________
> From: autodock-bounces at scripps.edu [autodock-bounces at scripps.edu] on 
> behalf of Oleg Trott [trott at scripps.edu]
> Sent: Monday, April 14, 2014 10:44 AM
> To: autodock at scripps.edu
> Subject: Re: ADL: Vina: docking results dependent on ligand input
conformation?
>
> Hi
>
> The probability distribution of the results coming from Vina should 
> not depend on the input ligand's conformation (position, orientation 
> and torsions). In other words, its results should be unbiased w.r.t.
> the input. (This is a quality many, if not most, docking programs
> lack)
>
> This is not quite the same as saying that the individual results do 
> not depend on the input, because they are merely samples from the 
> above distribution. These samples will depend on the random seed, and 
> similarly, they may be affected by any changes in the input.
>
> Oleg
>
> On Mon, Apr 14, 2014 at 5:03 AM, Juan Munoz-Garcia 
> <juan.munoz-garcia at bioch.ox.ac.uk> wrote:
>> Hi,
>>
>> could any of the experts of Autodock Vina please tell me if they've seen
any dependencies of docking results on the input conformation of the ligand?
I've seen this with other scoring functions, specially for known low
affinity ligands, so that to minimise this effect I submitted and ensemble
of randomly generated conformations of each ligand. Would you suggest to do
the same with Vina?
>>
>> Thank you.
>> Regards.
>>
>> Juan C. Munoz-Garcia, PhD
>> Biomembrane Structure Unit
>> University of Oxford
>> South Parks Road
>> Oxford OX1 3QU
>> juan.munoz-garcia at bioch.ox.ac.uk
>>
>>
>>
>>
>> ________________________________________________
>> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list 
>> ---
>
>
>
> --
> Oleg Trott, Ph.D. (Columbia University)
>
> Staff Scientist in the Olson Lab
> The Scripps Research Institute
>
> http://olegtrott.com
>
> ________________________________________________
> --- ADL: AutoDock List  --- http://autodock.scripps.edu/mailing_list 
> ---
>
>
> ________________________________________________
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> ---



--
Oleg Trott, Ph.D. (Columbia University)

Staff Scientist in the Olson Lab
The Scripps Research Institute

http://olegtrott.com

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