Nature 410, 417 (2001) Macmillan Publishers Ltd.

Laws of form revisited

MICHAEL DENTON AND CRAIG MARSHALL

Michael Denton and Craig Marshall are in the Department of Biochemistry,
University of Otago, PO Box 56, Dunedin 9001, New Zealand.
 

Before Darwin, most biologists adhered to a platonic model of nature. This
implied that the biological realm consisted of a finite set of essentially
immutable natural forms that, like inorganic forms such as atoms or
crystals, are an intrinsic part of the eternal order of the world. Just
as, today, we account for the form of atoms and crystals by a set of
physical laws or 'constructional rules', so pre-darwinian biologists
sought to account for the origin of biological forms in terms of a set of
generative physical laws often referred to as the 'laws of form'.

For many biologists today, platonic biology is an anachronism
irretrievably laid to rest, and the idea that biological forms might be
intrinsic features of nature generated by physical laws is treated with
incredulity. However, recent advances in protein chemistry suggest that at
least one set of biological forms  the basic protein folds  is
determined by physical laws similar to those giving rise to crystals and
atoms. They give every appearance of being invariant platonic forms of
precisely the type that the pre-darwinian biologists were seeking.

Protein folds, the basic constructional units of proteins, each consist of
a folded chain of between 80 and 200 amino acids. Some proteins consist of
a single fold, but most are a combination of two or more. During the
1970s, as the three-dimensional structure of an increasing number of folds
was determined, it became apparent that the folds could be classified into
a finite number of distinct structural families containing a number of
closely related forms. The fact that protein folds could be classified in
this manner provided the first line of evidence that the folds might be
natural forms.

Further evidence that the folds do indeed represent a finite set of natural forms is
provided by detailed structural studies carried out over the past two
decades which have revealed that the structure of the folds can be
accounted for by what amounts to a set of 'constructional rules' governing
the way that the various secondary structural motifs, such as -helices and
-sheets, can be combined and packed into compact three-dimensional
structures. One is inevitably reminded of the atom-building rules
governing the assembly of subatomic particles into the 92 atoms of the
periodic table.

Consideration of these 'constructional laws' suggests that the total
number of permissible folds is bound to be restricted to a very small
number - about 4,000, according to one estimate. Confirmation that this is
probably so is provided by a different type of estimate, based on the
discovery rate of new folds. Using this method, Cyrus Chothia of Britain's
Medical Research Council estimated that the total number of folds utilized
by living organisms may not be more than 1,000. Subsequent estimates have
given figures of between 500 and 1,000. Whatever the final figure, the
fact that the total number of folds represents a tiny stable fraction of
all possible polypeptide conformations, determined by the laws of physics,
reinforces the notion that the folds, like atoms, represent a finite set
of built-in natural forms.

The robustness of the folds offers another clue. The fact that the folds
can retain their native conformations in the face of multiple different
sorts of short-term deformations caused by the molecular turbulence of the
cell, and in the face of extensive, long-term evolutionary changes in
their amino-acid sequences, is precisely what would be expected if they
are natural forms, specified by physical law. Again, the fact that the
same fold can be specified by many different, apparently
unrelated amino-acid sequences, suggesting multiple separate discoveries
during the course of evolution, is further evidence that the folds are
intrinsic features of the order of nature. Finally, the fact that in many
cases the same fold is adapted to very different biochemical functions
is precisely what would be expected if protein functions are secondary
adaptations of a set of primary, immutable, natural forms.

If forms as complex as the protein folds are intrinsic features of nature,
might some of the higher architecture of life also be determined by
physical law? The robustness of certain cytoplasmic forms, for example the
spindle apparatus and the cell form of ciliate protozoans such as Stentor,
suggests that these forms may also represent uniquely stable and
energetically favoured structures specified by physical law.

If it does turn out that a substantial amount of higher biological form is
natural, then the implications will be radical and far-reaching. It will
mean that physical laws must have had a far greater role in the evolution
of biological form than is generally assumed. And it will mean a return to
the pre-darwinian conception that underlying all the diversity of the life
is a finite set of natural forms that will recur over and over again
anywhere in the cosmos where there is carbon-based life.

References
 1.   Chothia, C. One thousand families for the molecular biologist. Nature 357, 543-544 (1992). | PubMed |
 2.   Chothia, C. & Finkelstein, A. V. The classification and origins of protein folding patterns. Ann. Rev. Biochem. 59, 1007-1039 (1990). | PubMed |
 3.   Lindgard, P. & Bohr, H. How many protein fold classes are to be found? in Protein Folds (eds Bohr, H. & Brunak, S.) 98-102 (CRC Press, New York, 1996).
 4.   Kirschner, M., Gerhart, J. & Michison,T. Molecular 'Vitalism'. Cell 100, 79-88 (2000). | PubMed |
 5.   Orengo, C. A., Jones, D. T. & Thornton, J. Protein superfamilies and domain superfolds. Nature 372, 631-634 (1994). | PubMed |
 

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