QUESTIONS: alpha-helix "signals" in proteins
Simon Brocklehurst Bioc
smb18 at mole.bio.cam.ac.uk
Sat Jul 9 05:02:54 EST 1994
As I have hinted in previous posts, I thought that we all may have been
talking at cross purposes. As the discussion as gone on, it seems even
clearer to me that this is so. I think we actually agree on a lot
of points, but there are some differences.
So first, let me try to put _clearly_ the situation as I see it,
which will, at the least, clarify my position (I hope). Along the way,
I'd like to turn the discussion around and pose a couple of questions about
why people think this argument is important.
Here goes (sorry for the length of this post)!
WHAT ARE KINETIC AND THERMODYNAMIC CONTROL (according to me that is!)
First it might be useful to clarify what _I mean by "kinetic control"
and "thermodynamic control". A picture is useful here (T.S. means
transition state, I. means intermediate). Note there are no axes drawn,
but it's the usual energy vs reaction coordinate type stuff.
T.S. 2. ____
T.S. 1 ____
Start State ___
End State 1____
End State 2. ___
So, from the start state, we go via T.S. to the intermediate I.
Then from this common intermediate we can either go to End state 1, or
End state 2.
Under conditions when End State 1 is _NOT_ in rapid equilibrium
with I. , then End State 1 will be favoured over End state 2, 'cos
T.S. 1 is of lower energy than T.S. 2. This is kinetic control.
Under conditions when End State 1 IS in rapid equilibrium with I,
then the End State 2 will be more favoured. This is thermodynamic
In general, different physical conditions (e.g. temperature) can
induce a switch between these two possibilities.
HOW DOES THIS APPLY TO PROTEIN FOLDING?
In answering this question, we see that we have a problem right away.
In terms of the above scheme, Start State is obviously the unfolded state.
But in Nature, we observe basically only one End State - the folded state.
So you could say that it's not even relevant to ask the question
about kinetic vs thermodynamic control (in the way I have asked it) in the
first place because we don't observe a mixture of End States under most
But if one was determined to ask the kinetic/thermodynamic question
about protein folding, what vaguely sensible things can we say?
Well for one thing, we should ask what the consequences are of saying
that thermodynamic control is what we're observing. I think the
most dangerous thing about this is that you will get a whole bunch of
people thinking that this means that the native state of a protein
is the GLOBAL MINIMUM conformation.
On the other hand, what are the consequences of saying that folding
is kinetically controlled? Well, the only thing I can think that this
can mean in the context of protein folding is:
"Proteins fold to the lowest energy state that is kinetically
accessible on the folding pathway"
That is there could be other low energy End states, but we
don't observe them cos the transition states through which they
would have to go are of too high an energy.
I have to say that I think that this is quite a good description
of folding! The advantage it has over the thermodynamic control description
is that by using this definition, you make it crystal clear that you don't
preclude the possibility that there is a lower energy conformation somewhere
that we just don't observe.
CONCLUSIONS AND QUESTIONS
After all this, I still don't understand the businees about the
"folding pathway being irrelevant to the native state". I would
like to ask everyone (Ken particularly) this question:
Do people out there think that the GLOBAL energy minimum
conformation of a polypeptide chain is the native folded conformation
that we observe?
If not, why does it matter whether protein folding is
thermodynamically controlled or kinetically controlled?
The final question I would like to ask is: what bearing do these
arguments have for predicting the three-dimensional structure of
a protein for it's amino-acid sequence?
Sorry for the length of this post - but I hope some things are
a but clearer now!
| ,_ o Simon M. Brocklehurst,
| / //\, Oxford Centre for Molecular Sciences,
| \>> | Department of Biochemistry, University of Oxford,
| \\, Oxford, UK.
| E-mail: smb at bioch.ox.ac.uk
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