Subject: Autodock result not consistent with crystal structure

From: "[email-masked]" <[email-masked]>
Date: Tue, 7 May 2002 05:48:19 -0400

Hi CCLers,

I'd like to hear from anybody who's used Autodock regarding the results I'm getting. I docked a ligand which was taken out of a crystalized ligand-protein complex and used it to dock into the binding site. I tested with rigid docking and it works well but when the ligand is flexible, I got a whole lots of conformations which don't really produce the crystalized binding mode very well. At most one 3 or 4 conformations only will have better conformations (compare to the crystal structure), with different binding affinity. Whatever the case, the lowest binding affinity calculated is still found in the binding site, just that the frequency of this conformation is not high. 

I don't quite understand why this happened, aside from the fact maybe the force field wasn't suitable ( I used CVFF) or maybe the ligand has different binding modes. The total charge on my protein is negative while the ligand is positive. Does anybody have this sort of problem or am I just not using Autodock correctly. I tried many times with changing some parameters but the results are pretty much consistent.

Any feedback will be truly appreciated. Thanks.

Rowyna K.

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From: David van der Spoel <[email-masked]>
Date: Tue, 7 May 2002 12:34:32 +0200 (CEST)

On Tue, 7 May 2002, [email-masked] wrote:

>I'd like to hear from anybody who's used Autodock regarding the results 
>I'm getting. I docked a ligand which was taken out of a crystalized 
>ligand-protein complex and used it to dock into the binding site. I 
>tested with rigid docking and it works well but when the ligand is 
>flexible, I got a whole lots of conformations which don't really produce 
>the crystalized binding mode very well. At most one 3 or 4 conformations 
>only will have better conformations (compare to the crystal structure), 
>with different binding affinity. Whatever the case, the lowest binding 
>affinity calculated is still found in the binding site, just that the 
>frequency of this conformation is not high. 
>
>I don't quite understand why this happened, aside from the fact maybe 
>the force field wasn't suitable ( I used CVFF) or maybe the ligand has 
>different binding modes. The total charge on my protein is negative while 
>the ligand is positive. Does anybody have this sort of problem or am I 
>just not using Autodock correctly. I tried many times with changing some 
>parameters but the results are pretty much consistent.

There are two points to consider: force field accuracy and searching 
efficiency. Rigid docking is easier on the searching algorithm, so if you 
find the pocket there it means it can be found. However this is no 
guarantee that a flexible ligand would find the same site, even with 
infinite searching, since a flexible ligand might find other (lower) 
energy minima.

I have a paper coming up in Protein Science about the efficiency of 
docking using Autodock. We basically found that we could reproduce most 
crystal complexes (8 out of 10) with flexible ligands. It may need some 
parameter tuning (e.g. larger population size), however, and quite a bit 
of patience because some of these dockings took several 100 hours of CPU 
time.

 -- 
Groeten, David.
________________________________________________________________________
Dr. David van der Spoel, 	Biomedical center, Dept. of Biochemistry
Husargatan 3, Box 576,  	75123 Uppsala, Sweden
phone:	46 18 471 4205		fax: 46 18 511 755
[email-masked]	[email-masked]   http://zorn.bmc.uu.se/~spoel
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