Evolution and Protein Folds

Ram Samudrala ram at mbisgi.umd.edu
Fri Jun 24 17:43:11 EST 1994


Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:

> What you wrote is generally accepted as being correct.  Quite a lot
>is known about what kind of amino acid substitutions are acceptable in
>particular structural environments.

I am now confused as to what you mean by "acceptable".  Who decides
what is acceptable?  Remember, there's no selection on the protein
produced by the gene yet.  What's to prevent it from mutating a
residue in the hydrophobic core to an ASP and thereby destabilising
the fold by a few Cal? Given that there's no selection on this
protein, it doesn't seem to matter if it folds up or not.  But it
does, if it has to evolve to a new function.  Thus there is some
mechanism that makes sure a compact-fold is preserved.

>   Mutations are accepted at the level of the organism i.e.
>if the mutation causes only problems for the organism, then
>it (the organism) may not survive etc.

So how does a mutation that produces a misfolded protein be
disadvantageous?  Is the cost of recycling the misfolded protein
prohibitive enough to favour negative selection?

In any case, are there any numbers for such a thing?  How do our
current models explain the times of divergence of
haemoglobin/myoglobin? 

>    I don't know about this.  But there is no reason why it couldn't
>happen.  Surely it depends on what problems the lack of a particular
>protein causes for the organism.

Oh, the protein is just a copy of another one.  So there is one gene,
producing fully functional proteins.  The other gene is the one that
is mutation.  So there is no selective pressure on one copy of the
gene and it mutates at will in the hopes of finding a new function.
Now on the way, I claim it cannot have mutations that will destroy the
fold.  If it does, then it will a lot longer to get back on track.
What is the mechanism that ensures that no mutations that destroy the
fold (again, there's really no protein deficiency) are not selected
for?

--Ram

ram at elan1.carb.nist.gov                     Annihilation, kill 'em all!
     Capitulation, watch the mighty fall. The road to glory is lined in
 red, and the reason now is gone... the battle rages on! ---Deep Purple



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