Re: [asa] neutral enabling mutations

From: Terry M. Gray <>
Date: Thu Aug 23 2007 - 23:44:21 EDT


Here's how I see what you have presented here:

1. They determined the most likely ancient sequence based on
comparisons -- nothing controversial here -- similar to inferring the
text of ancient manuscripts based on comparison of variant texts.

2. Then, as I read it, they actually determined the structure of the
ancient protein, by synthesizing it, purifying, and determining its
structure using some structural biology method (most likely x-ray
crystallography--I'll check it out for sure but it may be the very
structural biology lab where I did my graduate work).

3. Once you have that structure--you can use a procedure known as
homology modeling for determining the structure of similar proteins--
ones that differ from the experimentally determined structure by only
a few amino acids residues of the sequence and using computational
methods to "determine" the structure of the protein.

4. By looking at the unique binding site--i.e. the cortisol binding
site--vs. the non-binding ancient version they noted three specific
amino acid substitutions that appear critical.

5. When these three are put into the ancient structure alone, it
appears from their comparisons and modeling of the structures that
these three would severely destabilize the ancient protein--unless
the "neutral enabling mutations" were already there to stabilize the
protein containing these changes in the binding site. They are
"neutral" because they are the kinds of mutations that don't normal
affect the folding or stability of the protein, i.e. the amino acid
side chains have similar physical properties (charge, polarity, bulk,
hydrophobicity, etc.)

To me this is an interesting but relatively non-controversial result--
the unique and very interesting part is the actual production of the
ancient protein and the determination of its binding properties and
its stability. Doing this was probably necessary for determining
whether or not the "neutral, enabling mutations" actually did
anything important. Otherwise, how would you know they weren't just
ordinary "neutral" mutations.

Hopefully, I'm not just saying the same thing over again so that my
explanation is just a confusing as that which I'm trying to explain.
Let me know if I haven't unpacked the part that isn't clear.

The discussion of the road not taken and re-running of the
evolutionary clock, like Gould's original discussion in Wonderful
Life, delves into metaphysical questions that depend in many ways on
your view of nature and God's interaction with nature. From an
evolutionary biology perspective it's sort of a no-brainer. Of
course, future change is dependent on previous change and had the
previous change not happened the future change may not happen. Thus,
there is chance and contingency in evolution. Hardly anybody who is
an evolutionist (even of the TE variety) denies that.

However, this says absolutely nothing about God's involvement. (God
can be involved in chance and contingent events--at least if you're a
Calvinist!) My response to Gould has always been--if we play the tape
again, we get exactly the same result--not because of anything in the
physics, chemistry, biology, astronomy, or history (so from a
"scientific" perspective we might be tempted to say that it would
turn out different). We get the same result because God would govern
those natural processes (even those involving randomness and
contingency) to produce the same result.


On Aug 23, 2007, at 8:21 PM, Randy Isaac wrote:

> This appeared in Science News today. It's a subscription only site
> so I'm copying the article instead of the link. I'd appreciate some
> help from the biochemists on this list in understanding what was
> done and what the implications are. They use the word "inferred" a
> lot so it seems rather speculative.
> Some of you may have access to the original article at http://
> I don't understand how they can infer the change in structure, much
> less the conclusions they draw. And the term "neutral enabling
> mutations" seems a little oxymoronic. But that may just mean I
> don't understand it.
> Randy

Terry M. Gray, Ph.D.
Computer Support Scientist
Chemistry Department
Colorado State University
Fort Collins, CO 80523
(o) 970-491-7003 (f) 970-491-1801

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Received on Thu Aug 23 23:44:41 2007

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