3D-proteine structure according to available DNA-sequence

Phil Jeffrey phil at xtreme1.mskcc.org
Sat Jan 28 16:28:13 EST 1995


In article <D31CzC.DEL at rockyd.rockefeller.edu> sali at tamika.rockefeller.edu (Andrej Sali) writes:

>   In article <1995Jan26.200503.27941 at alw.nih.gov> johnk at spasm.niddk.nih.gov  
>   (John Kuszewski) writes:
>   > 
>   > Once and for all:
>   > 
>   > The folding problem isn't solved!
>   > 
>   > Modelling based on (very) related sequences with known structures is
>   > still very difficult and hardly a well-developed technique!
>   > 
>   > Talk to your local crystallographer or NMR spectroscopist
>   > if you want coordinates that didn't just come from your
>   > imagination.
>   > -- 
>
    (*** preceding parts of article deleted ***)
>   ... When sequence identity is about 40% or more, you can get a model by  
>   comparative modeling that is essentially equivalent to a medium resolution  
>   X-ray structure (2.5A; R=factor 25%). 
>
    (*** subsequent parts of article deleted ***)

I'm sorry to have to insert my 2 cents here, but this is COMPLETELY incorrect.
Having worked at a variety of resolutions in crystal structures, and done some
homology modeling myself, I have yet to see a model that corresponded to
anything better than a partially-refined 4.5 Angstrom resolution structure
(read this as approx. 3x the error level that Dr. Sali suggests).

I think that the term "essentially equivalent" is being stretched way too far
here - the overall fold will be correct, some conserved loops will
perhaps even be correct, but many of the side-chains and a significant portion
of the backbone will exhibit very substantial deviations from their "true" 
positions.

If one wants an *accurate* picture of one's molecule one should (to quote
John Kuszewski)

> Talk to your local crystallographer or NMR spectroscopist
> if you want coordinates that didn't just come from your
> imagination.

If one wants a rough idea of what one's structure might be *similar* to,
then one should just find something with known structure that has 40% or
more sequence identity to the target and take a look at it. I'm tempted to
beleive that half the world has homology to immunoglobulins and the rest to
proteases, anyway :)  <--- note the smiley...

I've heard claims that modeling could approach the resolution of crystal
structures for many, many years. I have yet to see anyone live up to that
claim.

Just couldn't let this one go by.....

Phil Jeffrey (a protein crystallographer)
--
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| Phil Jeffrey                                  |                             |
| X-ray/Computer Manager, Crystallography Lab   | If you lie to the compiler, |
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| phil at xray2.mskcc.org, p-jeffrey at ski.mskcc.org |     - Henry Spencer         |
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