protein folding

kresten no-sp at m.org
Mon May 28 02:16:31 EST 2001


[snip]

> In principle we "could", although since (from my outsider's perspective)
we
> don't understand all the forces involved -- the long-range forces driving
> protein folding -- we can't describe them. For some proteins I think ab
initio
> calculations have worked, or very nearly so.

I think that we certainly at some time will understand the physical and
chemical forces that determine the stability of a protein. However, I think
that we presently cannot evaluate the energy of a protein at a given set of
atomic coordinates and thus calculate its potential energy surface. That is,
we cannot evaluate the energy of a conformation precisely enough to
calculate the absolute minimum. However, the results from the IBM blue gene
calculations may prove me wrong. The research efforts that presently are put
into this field will, however, probably make this change within not to many
years. Therefore I think that the problem will become more and more limited
by computation capabilities. This is why I encouraged the original poster, a
mathematician, to enter the field since I think that the mathematics of
finding global minima is essential to the calculation of protein structure.

Your mentioning of long-range forces is a good example of the problems in
this field. The methods that are presently employed usually consist of
replacing the problem of solving Newton/Schrödinger or something like this
with the problem of solving simpler equtions. However, in theory there
should be no difference between long- and short-range forces. It is only
when we substitute simple expressions for complicated equations that people
think of concepts such as Z-scores and other often very unphysical forces.


[snip]

> Sorry! When I say that enzymes move among metastable local minima, I'm
> implying that thermal energy is the motive force. The experimental
> observations I have in mind range from the structural dynamics of simple
> enzymes during the catalytic cycle, and the multi-state conformational
changes
> of allosteric enzymes. For allosteric enzymes, the major rearrangements
are
> driven by the binding of effectors as well as of substrate. An early
example
> is the alternate conformations of enzymes like (I think) citrate synthase,
> which when substrate binds, closes its active site like a trap to exclude
> water and create the appropriate hydrophobic environment for catalysis. In
> fact, I'll bet that the driving force for most enzyme structure changes
will
> be found to be the difference between the binding energy of substrate and
> product. (Loosely speaking!)

In general I agree with the above. However, I think that the local minima
that you are speaking about will not differ substantially, neither in energy
or in structure, from the global minimum. The global minimum may in fact be
one of the minima along the path. Regarding the driving force I would
suspect that the substrate would bind to a low energy conformation and that
the structural changes in the enzyme is driven by a combination of thermal
energy and the energy released in the substrate -> product conversion. As a
subset of these reactions are of course those where, e.g. on of the
substrates is something like ATP.

Best wishes,
Kresten
ð
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