Protein Folding/ Complexity plus reductionism = ?

[Judith Rosen <***>]

In Response to Jack's comments, I have copied the protein folding part of
that paper of my father's (BioTheory) which I posted a few days ago. Some of
the questions Jack asked are addressed in the following:

(By Robert Rosen):
A.  PROTEIN FOLDING:
Traditional views of genetic "coding" suffice only to determine the primary
structure, or the sequence, of amino acids along a polypeptide.  To become
active, the polypeptide molecule must fold into a specific,
three-dimensional active conformation; acquire a tertiary structure.  For
various important reasons, it was necessary that this folding be a
spontaneous process, occurring without the need for further "information".
In other words, it was necessary that primary structure entail the tertiary,
active, functional structure.  The protein folding problem is basically the
attempt to carry out this entailment explicitly; to find an algorithm which
can predict the geometry of a folded protein from its primary structure
alone.

Reductionistic physics, and physical chemistry, claim to be able to address
this question directly, in terms of writing down a free-energy function for
the molecule, from primary structure alone, and then minimizing it.  Despite
a great deal of effort, this kind of approach has basically gotten nowhere
after nearly 35 years of trying; indeed, such efforts have only served to
expose the weaknesses of reductionistic approaches to biological function in
general.

Rosen, on the other hand, was led by theory to take a quite different
approach to this problem, based on morphogenetic considerations rather than
the free energies of physical chemistry.  It rests on results arising from
what initially seems like a quite different problem; what embryologists call
cell sorting.  This has to do with generation and stability of patterns
formed in populations of motile units, which possess differential affinities
for each other.  Such populations arise in many different contexts besides
embryology; in physics, for example, they are the basis for "phase
separations", and even phase transitions.  In the l960's, Rosen developed
the general models which solve such problems, at least phenomenologically.
He later realized they could be applied to protein folding problems by tying
together some of the sorting elements with inelastic string.

            Experience with such an approach has been quite interesting.
First, instead of the hundreds or thousands of independent variables, which
the conventional approaches based on physical chemistry mandates, there are
only a few; perhaps half a dozen.  This means tertiary structures can be
generated quickly; even with sub-optimal algorithms, a polypeptide can be
folded in half an hour, with accuracies comparable to any other approach,
according to conventional measures of such things.  Moreover, we can begin
to approach "inverse problems", which will involve generating primary
structures which fold to display pre-specified activities using these ideas,
which are simply inaccessible to other approaches.

Aside from its inherent interest, in biomedical and pharmaceutical
applications, the approach itself is broadly applicable far outside these
domains.  It basically shows folding to be an example of what is often
called a synergetic process, in which only a few degrees of freedom control
hundreds or thousands of others.  Biology is replete with such processes,
which are only obscured, perhaps beyond salvation, by reductionistic
approaches to them.  We would desire to (but are presently incapable of)
incorporating such synergetic capabilities into our technologies (say in the
design of robots).  A study of protein folding from the above perspective
has already revealed a few necessary conditions, of general applicability,
for such synergies to be manifested.

Indeed, this entire story itself exemplifies the benefits of beginning from
an adequate theoretical foundation, and of how that foundation itself
provides the vehicle for transporting ideas far beyond the original context
for which they were developed.  In particular, ideas from morphogenesis
(developmental biology) were initially exported to problems of spatial
organization (folding) in large molecules, and then, by virtue of the
synergies manifested in them, to the general control problem of coherently
manipulating many degrees of freedom with a few controls.