[Chimera-users] Ligand Binding to Homodimeric Proteins

[Nancy]

Hi Elaine,

Thank you very much for your detailed reply.

Nancy



On Sun, Jan 17, 2010 at 8:49 PM, Elaine Meng <meng at cgl.ucsf.edu> wrote:

> 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
>>
>>
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