In article <2vhh69$at6 at news.doit.wisc.edu> kenp at banyo (Kenneth Prehoda) writes:
Simon Brocklehurst (Bioc) (smb18 at mole.bio.cam.ac.uk) wrote:
: Maybe we're talking at cross purposes, 'cos I should have
: thought that this is extremely relevant to the kinetic/thermodynamic
: argument.
: >Between the native and unfolded states
: >thermodynamic control still holds (i.e. it is path _independent_).
: >I don't see how you can argue that the folding pathway is
: >important without having multiple native states. Where are
: >these other states???
: They're kinetically inaccessible. That is, if you don't have
: transition states of sufficiently low energy to allow the protein to
: pass through them, then you won't get to a particular energy minimum
: (native state).
That's my point - they're kinetically inaccessible (in most cases) if
they are there at all. So of what importance are they?
That's exactly what kinetic control means--that the distribution of
products of a reaction (in this case folding) is not in accord with
the equilibrium distribution due to kinetic considerations. Part of
the importance of such states, if they do exist, is that
they would imply that thermodynamic stability is no guaranty that a
state will be assumed by a protein. According to this hypothesis,
proteins are specifically "designed" to have folding
pathways. The lack of a reasonably fast pathway would mean failure to
fold, despite thermodynamic stability. I'm not saying that this
hypothesis is correct, only that it is meaningful and plausible.
One way to think about the question is to ask whether there
could be mutations which, without destabilizing the folded state,
make the folding process so slow that folding is not observed.
I remember something about ts mutants which don't fold at the
restrictive temperature, but, if folded at the permissive temperature,
remain stable at the restrictive temperature. If such mutations
are not rare aberrations, but common ways of breaking a refined
function, then the kinetics of folding are quite important.
To put it
another way, do you believe it is valid to use equilibrium constants
when studying protein systems?
Certainly in some contexts. It must be true that the native state
is (under native conditions) favored over the unfolded state
(otherwise we'd never call it the folded state, it would just be
one of the substates of unfolded protein). However, if Simon
is right, then application of equilibrium constants to determine
which state is thenative state would sometimes lead you to false conclusions.
You would conclude that the (hypothetical) more stable, kinetically
inaccessible state was the native one.
Josh Cherry
cherry at watneys.med.utah.edu
