Kresten <kresten at my-deja.com> wrote:
>[snip]
>>>>> It is generally asumed that proteins usually do indeed fold to the
>> global minimum of Gibb's free enthalpy, and this is experimentally
>> well supported for many of them (though there may be exceptions - but
>> I'm currently not aware of any).
>>I think the work by Agard on alpha-lytic protease suggests something
>like this.
Isn't that the protein whose folding is catalysed by a part of itself,
the Pro-region? If this is true, then that does not argue against my
statement. I think that the fold, that the protein adopts, is the
global minimum of the molecule _with_ its Pro-region. After the
Pro-region is cleaved, the global minimum is elswhere in the fold
space, but it is kinetically inaccessible. Thus, the native protein
does not adopt its global minimum, but it *folds*to* the global
minimum. From the point of view of someone who wants to do something
with this protein, you may say that this makes no difference. But from
the point of view of someone reasoning about the principles of protein
folding, it does.
>Then there's the whole prion/amyloid discussion which is far
>from being solved.
No, IMHO this is a different issue. The statement, that the native
fold of a protein is its global minimum, is of course only valid as
long as it is soluble. The fold that an individual molecule adopts in
amyloid or other aggregates is surely energetically disfavored
compared with its native fold, but the fibril as a solid, the "phase
amyloid", is more stable than the soluble folded form. Again, one
might say that here the folded form isn't the most stable one. But
this is just another opportunity to put the statement more precisely:
The native folded form is the global minimum under certain conditions,
the "native conditions". (not the most precise term, I admit...)
The point is:
Nobody has ever argued that proteins wouldn't coagulate, unfold or
aggregate under certain conditions; but it *has* been argued that the
folding process is kinetically controlled and ends up in the
kinetically best accessible minimum, no matter wether this is the
global one or not. If this where true, it wouldn't make any sense to
try to compute the native fold in a systematic way, be it calculation
of the energy of every conformation with semiempirical methods, be it
the Schrödinger Equation. The only theoretical way to predict a fold
would be to mimic the *folding*process* in the computer - perhaps even
the involvement of the ribosome, chaperones etc. And structure
prediction by homology, without knowing a whole lot about the
principles of this kinetic control, would also be much less
succesfull.
So what I wanted to say that _if_ you put a protein into the right
conditions to fold, it will fold into the global minimum of free
energy, and not into some kinetically well accessible minimum. Of
course ther are other conditions where it does different things - and
e.g. the conformation in amyloid might well be kinetically controlled
(namely, the conformation where aggregation/fibril formation is
fastest).
Bye, Frank
