[Chimera-users] Ligand Binding to Homodimeric Proteins

[Elaine Meng]

Hi Nancy,
This is a general modeling question, not a Chimera question (since  
Chimera doesn't do automated docking) and would be better sent to a  
general forum such as ccl.net

However, I'll attempt a brief and necessarily general answer.

(a) It could be that the two binding sites are slightly different.   
This would not necessarily represent errors in the coordinates;  
perhaps the crystallization environment introduces slight  
asymmetries, or perhaps the two binding sites have some positive or  
negative cooperativity.

(b) Even if the binding sites are "really" symmetrical, very small  
differences in coordinates, well within experimental uncertainty even  
at high resolutions, could cause large differences in the results.   
Say one atom is shifted by 0.001 A -- that could cross some cutoff in  
the method and prevent the ligand from fitting into one copy of the  
site.

(c) Even if the coordinates for the two binding sites are exactly the  
same, there may be asymmetries introduced by how the docking program  
describes the sites or how it docks ligands into the sites.  For  
specifics, you would have to look at the documentation for that  
program, or contact its support address, if any.

I hope this helps,
Elaine
-----
Elaine C. Meng, Ph.D.
UCSF Computer Graphics Lab (Chimera team) and Babbitt Lab
Department of Pharmaceutical Chemistry
University of California, San Francisco

On Jan 17, 2010, at 5:14 PM, Nancy wrote:

> Hi All,
> I am performing molecular docking simulations of a ligand binding  
> to a homodimeric protein, to determine a potential binding site 
> (s).  Due to the symmetrical nature of a homodimer, I would expect  
> that the binding site(s) on one protomer would be identical on the  
> other protomer.  Therefore, a ligand should bind with equal  
> probability and affinity to both sides of the protein.  However,  
> when I perform a molecular docking simulation (using an X-Ray  
> crystal structure), the ligand preferentially binds to one side of  
> the homodimer.
>
> Is this outcome likely the result of errors inherent in the X-Ray  
> crystal structure, as one would expect identical binding to both  
> sides?
> Thank you very much.
> Nancy
>