protein folding

Dr. Peter Gegenheimer pgegen at ku.nolospamare.edu
Fri May 25 22:19:23 EST 2001

On Mon, 21 May 2001 11:28:20, "kresten" <no-sp at m.org> wrote:

ð (1) Why shouldn't we be able to "describe" the potential energy function, at
ð least for some subspace of the conformational space.

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.

ð (2) I have argued before that we may never know for sure whether proteins
ð attain their global minimum (without breaking bonds!) in their native fold.
ð However, in almost every known case there is no reason whatsoever to assume
ð that the Anfinsen hypothesis (proteins fold to their energy minimum) is not
ð true. If you think this isn't the case, please explain why.

I explained, [in my previous post] why I think so. The jist of my argument is
what you quote below:

ð > In particular, (2) is biologically meaningless, because a protein in its
ð > global minimum would not be capable of assuming different conformations
ð > without an external input of energy.

You said:
ð Take a simple organic molecule and look at it's rotational or vibrational
ð spectrum. It vibrates. It rotates. However, it's average structure is most
ð probably the global energy minimum. However, where there is life there is
ð always thermal energy available. In other cases enzymes may require
ð additional energy e.g. from ATP hydrolysis in order to carry out their
ð function.

The energy barriers for a small molecule are lower and fewer than for a
biological macromolecule. To me, this is a major difference -- along with the
fact that the permissible temperature range for biological polymers is
extremely narrow.

I also said:
ð > The proper functioning of most or all
ð > enzymes, for example, requires that they alternate between different
ð > 3-dimensional conformations. In other words, enzymes must exist in
ð >  metastable local energy minima.
ð How would such a mechanism work? What would make these proteins change
ð between their different local minima. If these proteins never get any
ð external energy as you suggest why do they not end up in a global minimum
ð where they - according to your statement - would be inactive. I think what
ð you are suggesting is a perpetuum mobile. Please correct me if I
ð misunderstand you.

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!)

| Dr. Peter Gegenheimer       | Vox: 785-864-3939  FAX: 785-864-5321   |
| Department of               |   PGegen at KU.nospam.edu                 |
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