posted 09. March 2003 15:02                   

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Before the Darwinian revolution many biologists considered organic forms to be determined by natural law like atoms or crystals and therefore necessary, intrinsic and immutable features of the world order, which will occur throughout the cosmos wherever there is life. The search for the natural determinants of organic form, the celebrated ‘‘Laws of Form’’. was seen as one of the major tasks of biology. After Darwin, this Platonic conception of form was abandoned and natural selection, not natural law, was increasingly seen to be the main, if not the exclusive, determinant of organic form. However, in the case of one class of very important organic forms, the basic protein folds, advances in protein chemistry since the early 1970s have revealed that they represent a finite set of natural forms, determined by a number of generative constructional rules, like those which govern the formation of atoms or crystals, in which functional adaptations are clearly secondary modifications of primary ‘‘givens of physics.’’ The folds are evidently determined by natural law, not natural selection, and are ‘‘lawful forms’’ in the Platonic and pre-Darwinian sense of the word, which are bound to occur everywhere in the universe where the same 20 amino acids are used for their construction. We argue that this is a major discovery which has many important implications regarding the origin of proteins, the origin of life and the fundamental nature of organic form . We speculate that it is unlikely that the folds will prove to be the only case in nature where a set of complex organic forms is determined by natural law, and suggest that natural law may have played a far greater role in the origin and evolution of life than is currently assumed.

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The widespread belief that organicforms are lawful ‘‘givens of nature’’ explains why it was that throughout the pre-Darwinian period from the naturphilosophie of the late 18th century, right up to the period just before the publication of the Origin, although it was universally accepted that organisms exhibited functional adaptations, for Goethe, Carus Goeffroy and Owen, it was always form which was of primary concern. Form came .first and function was viewed as a secondary and derived adaptive feature (Russell, 1916; Richards, 1992).

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The Platonic biology of the pre-Darwinian era with its emphasis on evolution by natural law and its conception of a rational order underlying the diversity of life, represented a grand scientific vision, whose heroic goal was nothing less than the unification of biology and physics. It collapsed primarily because it failed to identify the elusive laws of form which might have provided a rational account of organic form and explained how the evolution of the basic invariant forms or types, from cell forms to the body plans of the major phyla, and deep homologies such as the pentadactyl limb, might have come about as a result of natural law. That they had no convincing explanation was explicitly conceded by Owen (1849) in the .final
paragraph of ‘‘On the Nature of Limbs’’: ‘‘To what natural laws or secondary causes the succession and progression of such organic phenomena may have been committed we as yet are ignorant.’’

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Of course no serious biologist doubts that some biological forms may be given by natural law and arise spontaneously out of the intrinsic self-organizing properties of their constituents and may not need any genetic program for their specification. The spherical form of the cell and the .at form of the cell membrane are two well known examples. Other more complex examples cited by Waddington (1962) are the various cytoplasmic structures made up of multiple layers of membranes such as the grana and intergrana regions of chloroplasts, the hexagonal arrangement of the rhabdomeres in the eyes of insects and the many forms described by Thompson (1942) in Growth and Form, including radiolarian skeletons, the shapes of mollusk shells, the curved shape of animal horns. But on the whole, natural law is considered to play a very trivial role in the generation of biological form and particularly in the generation of complex seemingly asymmetric biological forms such as protein folds, cell forms, body plans, etc.

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The protein folds are the basic building blocks of proteins and therefore of the cell and indeed of all life on earth. Each is a polymer between 80 and 200 amino acids long consisting of from about 1000 to 3000 atoms folded up into a complex intricate three-dimensional shape. Most folds exhibit a hierarchical structure composed of basic secondary structural elements such as a helices and b sheet conformations which are often arranged into more complex motifs which are in turn combined together to make up the native conformation of the fold.

It is important at this stage to note that the great majority of functional proteins in the cell consist of two or more basic folds linked together into multidomain or multifold complexes. In this paper we are considering only the fundamental nature and evolutionary origin of the folds and not of the higher order adaptive structures into which they are combined. These higher order complexes resemble, ‘‘Lego-like’’-,contingent assemblages put together by natural selection for various biological functions during the course of evolution by gene duplication and fusion (Brandon & Tooze, 1999).

Despite these early successes the lack of any apparent regularity in protein structures, and the great dissimilarity among those that had been determined, provided no basis for a rational classification (Ptitsyn & Finkelstein, 1980; Richardson, 1981). The picture was still in those early days compatible with the Lego model, that the folds in living organisms on earth might be individual members of a near infinite set of contingent material assemblages put together by natural selection over millions of years of evolution. It was only during the 1970s, as the number of 3D structures began to grow significantly, that it first became apparent that there might not be an unlimited number of protein folds, that the folds might not belong to a potentially infinite set of artifactual Lego-like constructs. On the contrary, it became increasingly obvious as more structures were determined that the protein folds could be classified into a .finite number of distinct structural families containing a number of related but variant forms, i.e. that the classification system of fold structures was typological (Ptitsyn & Finkelstein, 1980; Richardson, 1981; Orengo et al., 1997). This was an important finding as the very fact that protein folds can be grouped in such a way was itself significant, for it provided the .first line of evidence that the folds might be natural forms determined by physical law.

It also became apparent that the 3D structures of individual folds were essentially invariant, some such as the Globin fold and the Rossman fold for example, having remained essentially unchanged for thousands of millions of years. Both their invariance and the typological classification schemes into which they could be grouped argued for their being a .finite set of ‘‘real timeless structures’’ determined by physics rather than being mutable ‘‘Lego-like’’ aggregates of amino acids determined by selection.

Consideration of the various physical constraints which restrict the folded spatial arrangements of linear polymers of amino acids, the laws of fold form, suggests that the total number of permissible folds is bound to be restricted to a very small number. One recent estimate based on possible arrangements of typical structural elements gave a maximum of 4000 folds (Lingard & Bohr, 1996). Based on similar considerations, the authors of another recent paper suggested that the maximum is likely to be no more than a few thousand (Chothia et al., 1997). A different type of estimate based on the rate of discovery of new folds, rather than permissible spatial arrangements, suggests that the total number of folds utilized by organisms on earth might not be more than 1000 (Chothia, 1993). In many recent reports the total number of different folds is often cited to be somewhat less than 1000 (Holm & Sander, 1996; Orengo et al., 1997; Zhang & DeLisi, 1999; Holm & Sander, 1999).

Whatever the actual 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 further the notion that the folds like atoms, represent a .finite set of allowable physical structures which would recur throughout the cosmos wherever there is carbon-based life utilizing the same 20 amino acids.

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Further evidences consistent with the Platonic conception that the protein folds represent a set of lawful immutable natural forms, ‘‘primary givens of physics,’’ are those many cases where protein functions are clearly secondary adaptations of a primary, immutable form (Gerlt & Babbitt, 2001). This is spectacularly true in the case of some of the more common folds also known as superfolds (Orengo et al., 1994; Gerlt & Babbitt, 2001). In the case of one superfold the so-called triosephosphate isomerase (TIM) barrel, an eight-stranded alpha/beta bundle (see Fig. 1), essentially the same fold, has been secondarily modified for many completely unrelated enzymic functions occurring in such diverse enzymes as triosephosphate isomerase, enolase and glycolate oxidase (Orengo et al., 1994). Another example, where a basic fold has been secondarily modified for various biochemical functions, in this case closely related functions, is the various elegant functional adaptations to oxygen uptake and carriage exhibited by the globin fold in myoglobin and the various vertebrate hemoglobins. The fact that in many cases where the same fold is adapted to different functions, no trace of homology can be detected in the amino acid sequences, suggesting multiple separate discoveries of the same basic structure during the course of evolution (Orengo et al., 1994; Brandon & Tooze, 1999), further reinforces the conclusion that the folds are a .finite set of ahistoric physical forms.

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posted 10. March 2003 00:43                   

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During folding the amino acid sequence of a protein appears to be searching conformation space for increasingly stable intermediates which lead it step wise toward the deepest energy minimum for that sequence, which corresponds to its .final native conformation (Ptitsyn & Finkelstein, 1980; Finkelstein & Ptitsyn, 1987). The process is driven thermodynamically via a succession of free energy decreases (Dinner et al., 2000). The process of folding is often pictured as being analogous to a ball .finding its way down the sides of a complex rather irregularly shaped bowl to the bottom of the bowl, its .nal preordained and natural resting place, where the bottom of the bowl represents the natural free energy minimum of the fold. Extending this analogy we can think of there being a preexisting energy landscape containing 1000 or so uniquely shaped bowls or free energy minima. This picture lends itself to Platonic interpretation. Even the terms used in the literature reflect the Platonic concept of matter ‘‘.finding’’ or ‘‘filling’’ a pre-existing mold. Thus the folding process is often described as a mechanism by which ‘‘sequence selects structure.’’ As a recent author commented: ‘‘Thus the notion that sequence determines structure might be more precisely formulated with the concept that sequence chooses between the limited number of secondary structures available to the polypeptide backbone’’ (Honig, 1999). In other words, it is not the sequence which specifies the mold but the mold which specifies which sequences can be accommodated. For the mold is prior to the sequence, although of course during folding each particular sequence is prior in time to the form which it .finally makes manifest. The ubiquitous text book claim that ‘‘the amino acid sequence determines the 3D form of the protein’’ is a mechanistic interpretation of the folding process which might be more accurately stated Platonically as ‘‘the prior laws of form determine which amino acid sequences can fold into a stable 3D form.’’ If the sequence contains any information, it is not information to create or generate a unique artifact-like assemblage analogous to a Lego construct or a watch, but more of a guide through a preexisting Platonic landscape to an already prefigured end.

The free energy difference between the native conformation of the fold and its denatured state is small. A consequence of this is that folds are only marginally stable. This allows for a crucial degree of structural .flexibility, which is necessary for many catalytic and other functional activities, which often necessitate the fold adopting slightly different conformations. But it also means that because of the continual buffeting and bombardment arising from molecular collisions in the turbulent interior of the cell, the configuration of each fold is continually subject to conformational disturbances which may involve anything from the movement of a few atoms to the unfolding of sections of the amino acid chain (Brandon & Tooze, 1999). However a fold is able to maintain and regain its native conformation in the face of these microchallenges because its native conformation, being a natural free energy minimum, acts as a natural attractor ‘‘continually drawing’’ all the parts of the fold back into its proper native conformation (the natural free energy minimum of the fold). And just as a ball in a bowl always ends up at the bottom of the bowl, a fold is also able to get back ‘‘home’’ or to recover its proper conformation along an infinity of different paths. In short, the folds are robust natural existents, whose proper forms are under the governance and supervision of natural law. In the case of artifactual contingent assemblages of matter such as a watch or ‘‘Lego construct,’’ there is no natural agency or natural guarantor of ‘‘proper form’’, no eternally present Platonic mold or free energy minimum acting as an attractor continually drawing or guiding the assembly of its components to a preordained end. Consequently artifacts are not robust and are incapable of recovering their form after rearrangements of their components. Natural forms are robust, contingent artificial forms are fragile. In the case of natural forms, the agency of natural law acts ‘‘freely’’ as the guarantor of form. In the case of artifacts there is no such guarantor. These considerations highlight an interesting difference between natural and artificial forms. In the case of artifactual forms such as Lego assemblages or watches or other types of machines which are put together from the bottom up mechanically, we have an infinity of forms, but each is led up to or assembled by only a few or even only one unique constructional path. In the case of natural forms on the other hand, and the folds are classic examples, there is a finite number of forms but an infinite number of paths via which their actualization may be achieved.

The 3D conformations of the folds exhibit another sort of robustness, they are remarkably resistant to evolutionary changes in their amino acid sequences (Brandon & Tooze, 1999). As referred to above, although there are only a limited number of folds permitted by physics, many very different apparently unrelated amino acid sequences can fold into the same form (Gerlt & Babbitt, 2001). Because protein functions depend on the maintenance of a stable scaffold, the tolerance of the folds to sequential changes may well confer another crucial element of robustness making them ‘‘immune to most mutational insults’’ and hence evolutionarily reliable constructional units of the cell. The self-organization of the same fold from very different amino acid sequences again underscores the natural autonomy and Platonic primacy of the fold over its material constituents and highlights the fact that the folds are natural existents and not artifactual aggregates of matter like machines, which do not possess any natural autonomy over their components, and are far less tolerant of variations in their basic constituents.

We speculate that the fact that the robustness of the folds [which enables them to maintain their forms and dependent functions in the face of both mutational challenges and conformational disturbances due to the turbulence of the cell’s interior] is ‘‘natural’’ may have deep evolutionary implications. The robustness of biological systems is generally conceived of as being analogous to that of advanced machines utilizing such devices as feedback control, parallel circuitry, error fail-safe devices, redundancy and so forth (Keller, 2000; Kitano, 2002; Csete & Doyle, 2002). But such robustness which we suggest might be termed ‘‘artifactual robustness’’ is inherently complex and can only be arrived at after millions of years of evolution and is necessarily a secondary and derived feature of any biological system or structure. The robustness of the folds is a natural intrinsic feature of the folds themselves and not a secondarily evolved feature. Robustness of this sort is ‘‘for free’’ and does not require the intervention of natural selection. Such robustness has the enormous evolutionary advantage in that it provides evolution with ‘‘ready-made’’ stable structures upon which to build more complex structures and functions. We speculate that an element of natural robustness may be a necessary feature of all biological forms utilized by evolution from the molecular to the organismic level.

If the folds were contingent assemblages of matter like Lego constructs, watches or other sorts of artifacts, where the parts are the primary things and pre-exist the whole, then the various parts of each fold, the constituent a helices and b sheet conformations and higher order submotifs which make up the whole should be stable structures (like Lego bricks) which should exist prior to and independent of the wholes in which they occur. And if this were the case then the structure of the whole fold should be easily predictable (as in the case of an artifactual assemblage like Lego) from the character and properties of its parts in isolation. But this is evidently not the case. On the contrary, many of the unique secondary structural motifs which make up a mature fold are in most cases, either highly metastable outside the fold or non-existent. We can state this formally by saying that most submotifs which make up a fold are existentially dependent on being part of the native conformation of the whole fold, outside of which they have no independent existence. Evidence that the specific conformation adopted by particular segments of the amino acid chain is determined by the whole was gained some time ago in the classic complementation experiments of Anfinsen, which showed that the isolated S-peptide of ribonuclease, which comprises residues 1–20 of the enzyme, is a random coil in isolation, whereas most of it forms an a helix in combination with the rest of the molecule. Similarly, the fragments of myoglobin released from the molecule after cyanogen bromide treatment, the so-called peptides 1, 2 and 3, have very little residual secondary structure after their removal from the myoglobin molecule. Peptide 1 aggregates, peptide 2 is a random coil and the large central peptide, peptide 3, has only residual a helical properties Anfinsen, 1973). Evidently the structures adopted by the different sections of the amino acid sequence are ‘‘context dependent.’’ The case of the prion proteins illustrates again that the same sequence may fold into two alternative structures depending on context (Prusiner, 1995; Manson, 1999). Studies on the Arc repressor molecule (Cordes et al., 2000) have revealed that one section of the protein can switch from a helical to a sheet conformation depending on minor environmental changes, including temperature and solvent conditions. The fact that the same or very similar sequences may adopt different secondary structures dependent on context is at the heart of the whole problem of predicting the 3D structure of a protein from its amino acid sequence. If the same sequences always adopted the same structures whatever the context, if in other words the substructures of proteins were like the building blocks of Lego, or the cogs of a watch, then the problem of prediction of ‘‘global form’’ from the form of the building blocks would be easy, but of course this is not the case and the problem is far from solved.
The linguistic analogy again springs to mind. The meaning of a word in a sentence may vary depending on the sentence in which it occurs, its context. In a spoken sentence of English for example, the sound represented by the letters ‘‘rite’’ or ‘‘right’’ may refer from anything from a medieval ritual to a movement or a moral judgement. Outside the context in which it occurs it is impossible to determine its meaning. Consequently it is impossible to determine the meaning of a ‘‘whole’’ sentence from the study of its constituent words in isolation. Proteins, like sentences, are intensely holistic entities. All the current evidence suggests that the various parts of the fold, the various constituent a helices and b sheet conformations and higher order submotifs, exert what appears to be a mutual and reciprocal formative influence on each other and on the whole, which itself in its turn exerts a reciprocal formative influence on all its constituent parts. In this characteristic proteins are unlike any other material objects with which we are familiar.

If the folds are indeed lawful natural forms arising out of the intrinsic physic al properties of amino acid sequences, it is hard to see how selection for function can have played a significant role in their origin or evolution. The problem is somewhat like trying to provide a selectionist/functional explanation for the spherical shape of a cell, or the .at shape of the cell membrane! Selection may select a whole fold and then modify it for function and this is clearly

In the case of the folds, origin per saltum or in Finkelstein’s (1994) words ‘‘by choice from random [amino acid] sequences’’ is only a feasible mechanism if the protein folds are easy to find by chance and therefore common in amino sequence space. There is no doubt that individual a helices and b sheets are very common in sequence space and as the folds arise naturally from combinations of these subunits one might presume that the folds themselves would be relatively common. Whether they are or not has been a subject of considerable discussion (Finkelstein, 1994; Cordes et al.,1996; Sauer, 1996; Axe, 2000). Thermodynamic considerations of the random characteristics of fold sequences support the contention that stable folds are common in sequence space (Finkelstein & Ptitsyn, 1987; Finkelstein, 1994; Finkelstein et al., 1995). In Finkelstein’s (1994) words ‘‘little editing of a random sequence is necessary for the formation of the protein globule itself.’’ In libraries of random amino acid sequences, a helical proteins displaying cooperative thermal denaturation and specific oligomeric states have been recovered at frequences of 1% (Cordes et al., 1996). Evidence that different stable structures may be close in sequence space is supported by the case of the prion proteins and other cases where different structures may be adopted by the same sequence, such as the Arc repressor mutant, referred to above. Discussing the implications of the conformational switch in the Arc repressor the authors (Cordes et al., 2000) comment: ‘‘The intermediate can adopt either fold y Thus distinct protein folds need not be isolated islands in sequence space, but can be linked by evolutionary bridges where multiple

Another line of evidence which suggests that the folds must be relatively common in sequence space is the existence of overlapping genes. These appear to occur in the genomes of almost all organisms. New functional proteins could never have been discovered or evolved, embedded in existing gene sequences, if the folds were not relatively common in sequence space.

The current consensus view (Finkelstein, 1994; Plaxco et al., 1998; Brandon & Tooze, 1999) is that stable folds are in fact quite common in amino acid sequence space. Brandon & Tooze (1999) have even speculated that as many as one in a hundred random amino acid sequences may fold into a stable form. If indeed folds are that common in sequence space, occurring, say, at a frequency of one in a hundred random sequences, then, this might mean that wherever random polypeptides are synthesized anywhere in the cosmos, in the laboratory, in a pre-biotic soup or in a primeval cell, all the basic folds utilized by life on earth would be bound to be generated after only a few thousand trials. And this leads us to surmise that if at some stage in cellular evolution ‘‘random polypeptides’’ were synthesized in great numbers, then all the folds might have been discovered quite easily by chance. This would mean that in the right environment, just as atoms are assembled in the stars and crystals form when rocks cool slowly, so the protein folds would also be formed automatically, wherever conditions permitted the synthesis of any quantity of polypeptides to occur. And because the association of many proteins with their prostheticgroups is basically spontaneous, and does not require the intervention of an enzyme, this raises the possibility that many protein functions may also have been generated deterministically in the protocell without the necessity for selection, by the direct association of small organic compounds with particular protein folds. In effect this means that merely by synthesizing a few thousand random polypeptides in a ‘‘broth’’ containing the basic biochemicals used by life on earth, including enzymic prosthetic groups, all the necessary proto-functional enzymes needed for cellular metabolism might be generated per saltum by natural law. These primitive enzymes could then be .fine tuned by selection to generate the highly efficient enzymes of modern cells. In effect the origin and evolution of the protein-based biochemistry of modern cells may be ‘‘a free lunch.’’ Evidence that intermediary metabolism may also have been given deterministically in the protocell was obtained in a recent study (Morowitz et al., 2000) which concluded that: ‘‘The chemistry at the core of the metabolic chart is necessary and deterministic and would likely characterize any aqueous carbon based life anywhere it is found in this universe.’’

The alternative to per saltum models is to envisage physically determined ‘‘constructional series’’ or evolutionary pathways starting from say, a simple single a helix structure and leading via a series of small motifs to the .final fold. One example of a simple, two-step ‘‘constructional sequence’’ for the evolution of the classic TIM barrel from a half barrel was reported recently (Lang et al., 2000). But how feasible might such constructional pathways be in the case of many folds? In the case of some folds, the globin fold for example, no one has yet been able to provide a credible constructional sequence from simple motif to .final fold to show how the fold might have come about via a series of stable intermediate forms. Some folds, like perhaps the TIM fold, may lend themselves to construction from simpler motifs but this may not be true of all folds. Of course as any set of small stable motifs and constructional sequences in prefold space would also be a .finite set and very much given by physics, then such constructional sequences if they exist, would be no less ‘‘built-in’’ than the .final set of stable folds to which they lead. However as there would be different routes through this pre-fold space to the 1000 folds, there would inevitably be an element of contingency in the actual routes taken. Nonetheless, the 1000 protein folds would still represent a physically determined or ‘‘built in’’ bottle neck through which protein evolution had to pass and through which it would have to pass on any earth-like planet, where life uses proteins constructed out of the same 20 amino acids.

The discovery that the folds are natural forms, whose evolution is determined largely by physical law and which are bound to arise spontaneously, ‘‘for free’’, in any large set of random amino acid sequences, strongly supports the widely held belief among origin of life researchers (already mentioned above) that life is itself an inevitable end of chemistry, a phenomenon which is bound to arise in the correct environmental conditions, perhaps in space or perhaps on the surfaces of newly formed planets (Lehninger, 1982; De Duve, 1991; Sowerby et al., 2001). It also provides new support for the currently fashionable Anthropic view that the laws of nature appear to be .fine tuned for life (Barrow & Tippler, 1986; Denton, 1998; Davies, 2001). For the lawful nature of the folds provides for the .first time evidence that the laws of nature may not only be fine tuned to generate an environment .fit for life (the stage) but may also be fine tuned to generate the organic forms (the actors) as well, in other words that the cosmos may be even more biocentric than is currently envisaged!

The protein folds clearly represent a .finite set of about 1000 natural forms determined like atoms and crystals and other natural forms by the laws of physics. They can be classified into distinct structural types, their structures can be accounted for in terms of a rational morphology of constructional rules, they have remained invariant for billions of years, and in many cases their functional adaptations are clearly secondary modifications of what are evidently ahistoric primary forms. They are robust both in their capacity to resist long-term evolutionary mutational challenges and in their capacity to maintain and regain their proper form in the face of the destabilizing challenges posed by the buffeting and turbulence of the cell’s interior. Depending on their frequency in sequence space, their evolutionary origin may have occurred either by saltation, or via physically determined intermediates, in other words by pre-ordained constructional pathways. In short, they do not conform in any way to the Darwinian conception of organicforms as contingent ‘‘Lego-like’’ functionally contrived assemblages of matter. On the contrary, they are wonderful exemplars of the pre-Darwinian and Platonic conception of organicforms as abstract, lawful and rational features of the eternal world order, which will occur throughout the cosmos wherever the same 20 protogenicamino acids are used to make proteins.

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posted 10. March 2003 01:32                   

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Despite the practically unlimited number of possible protein sequences, the number of basic shapes in which proteins fold seems not only to be finite, but also to be relatively small, with probably no more than 10,000 folds in existence. Moreover, the distribution of proteins among these folds is highly non-homogeneous — some folds and superfamilies are extremely abundant, but most are rare. Protein folds and families encoded in diverse genomes show similar size distributions with notable mathematical properties, which also extend to the number of connections between domains in multidomain proteins. All these distributions follow asymptotic power laws, such as have been identified in a wide variety of biological and physical systems, and which are typically associated with scale-free networks. These findings suggest that genome evolution is driven by extremely general mechanisms based on the preferential attachment principle.

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Projection of the structure of the protein universe on genomes and quantitative analysis of the outcome seems to result in some unexpected insights into general principles of genome evolution. Remarkably, the size distributions of folds for the explored part of the protein universe and of domain families for all analysed genomes, as well as the distribution of the number of domain connections in multidomain architectures, are all described by the same type of mathematical functions, in which the power law appears as an asymptotic. This suggests that extremely general mechanisms of evolution, apparently based on the preferential attachment (proliferation) principle, are at work in all these contexts.

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The genomes of over 60 organisms from all three kingdoms of life are now entirely sequenced. In many respects, the inventory of proteins used in different kingdoms appears surprisingly similar. However, eukaryotes differ from other kingdoms in that they use many long proteins, and have more proteins with coiled-coil helices and with regions abundant in regular secondary structure. Particular structural domains are used in many pathways. Nevertheless, one domain tends to occur only once in one particular pathway. Many proteins do not have close homologues in different species (orphans) and there could even be folds that are specific to one species. This view implies that protein fold space is discrete. An alternative model suggests that structure space is continuous and that modern proteins evolved by aggregating fragments of ancient proteins. Either way, after having harvested proteomes by applying standard tools, the challenge now seems to be to develop better methods for comparative proteomics.

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Conclusions

Is protein structure and/or sequence space continuous, or has nature leaped when inventing folds and functions? If proteins were assembled from fragments, does this imply modularity of sequences and folds, as, for example, seen in short peptide fragments that regulate the targeting of proteins through the cell? Does the existence of short motifs or modules imply fragment assembly? I doubt that we have the data to unambiguously answer these questions. In fact, the evidence from analyses of entirely sequenced organisms is equally spread between pro and con ‘natura non facit saltus’.

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A “switch” mutant of the Arc repressor homodimer was constructed by interchanging the sequence positions of a hydrophobic core residue, leucine 12, and an adjacent surface polar residue, asparagine 11, in each strand of an intersubunit
b sheet. The mutant protein adopts a fold in which each b strand is replaced by a right-handed helix and side chains in this region undergo significant repacking. The observed structural changes allow the protein to maintain solvent exposure of polar side chains and optimal burial of hydrophobic side chains. These results suggest that new protein folds can evolve from existing
folds without drastic or large-scale mutagenesis.

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ABSTRACT Many seemingly unrelated protein families share common folds. Theoretical models based on structure designability have suggested that a few folds should be very common while many others have low probability. In agreement with the
predictions of these models, we show that the distribution of observed protein families over different folds can be modeled with a highly stretched exponential.
Our results suggest that there are approximately 4,000 possible folds, some so unlikely that only approximately 2,000 folds existing among naturally occurring proteins. Due to the large number of extremely rare folds, constructing a comprehensive database of all existent folds would be difficult. Constructing database of the most-likely folds representing the vast majority of protein families would be considerably easier. Proteins 1999;35:408–414. r 1999

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ABSTRACT Many biological proteins are observed to fold into one of a limited number of structural motifs. By considering the requirements imposed on proteins by their need to fold rapidly, and the ease with which such requirements can be fulfilled as a function of the native structure, we can explain why certain structures are repeatedly observed among proteins with negligible sequence similarity. This work has
implications for the understanding of protein sequence– structure relationships as well as protein evolution.

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In contrast to models that explain the limited number observed structural motifs by postulating a limited number possible motifs (7), in our model, essentially all structures possible, given the right set of interactions. It is the uneven probabilities of finding any particular structure that results the observation of relatively few folds. As a result, as more protein structures are solved, novel motifs will continue observed. This model would also predict that a few folds would be observed very frequently, while most other folds would observed only once in unrelated proteins. This seems to common phenomenon in the data base of known protein structures, as the work of Orengo et al. (4) indicates.

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posted 10. March 2003 12:20                   

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***********
The robustness of biological systems is generally conceived of as being analogous to that of advanced machines utilizing such devices as feedback control, parallel circuitry, error fail-safe devices, redundancy and so forth (Keller, 2000; Kitano, 2002; Csete & Doyle, 2002). But such robustness which we suggest might be termed ‘‘artifactual robustness’’ is inherently complex and can only be arrived at after millions of years of evolution and is necessarily a secondary and derived feature of any biological system or structure. The robustness of the folds is a natural intrinsic feature of the folds themselves and not a secondarily evolved feature. Robustness of this sort is ‘‘for free’’ and does not require the intervention of natural selection.
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What? Is it just me, or are they contradicting themselves? One the one hand, they say the robustness comes from evolution, and in the very next sentence they say it is a natural intrinsic feature that evolution can use. What gives?

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posted 11. March 2003 01:00                   

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Secondly, as I mentioned before, inferences to homology based on structural similarity become very shaky. The incredulous "why would a designer reuse this fold?" argument is been seriously damaged.

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posted 11. March 2003 01:27                   

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Structural biology and structural genomics are expected to produce many three-dimensional protein structures in the near future. Each new structure raises questions about its function and evolution. Correct functional and evolutionary classification of a new structure is difficult for distantly related proteins and error-prone using simple statistical scores based on sequence or structure similarity. Here we present an accurate numerical method for the identification of evolutionary relationships (homology). The method is based on the principle that natural selection maintains structural and functional continuity within a diverging protein family. The problem of different rates of structural divergence between different families is solved by first using structural similarities to produce a global map of folds in protein space and then further subdividing fold neighborhoods into superfamilies based on functional similarities. In a validation test against a classification by human experts (SCOP), 77% of homologous pairs were identified with 92% reliability. The method is fully automated, allowing fast, self-consistent and complete classification of large numbers of protein structures. In particular, the discrimination between analogy and homology of close structural neighbors will lead to functional predictions while avoiding overprediction.

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So perhaps disciplinary territorialism should not rule out Intelligent Design as a genuinely scientific explanation. But we are not out of the woods yet. For even though countenancing design
as an explanation might in principle count as genuine science, it cannot if the design hypothesis is not empirically distinguishable from explanations which appeal only to the natural powers of natural substances. If such empirical distinguishability is not possible, then there is no scientifically respectable way, by IDT’s own lights, to defend intelligent design as an explanation distinct from law and chance.

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posted 11. March 2003 03:26                   

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The question we need to ask is whether a structure (molecular or organismal) is similar because it shares a common ancestry and thus is homologous or because there is no (or very few) alternative. The former approach, of course, underpins most evolutionary thinking and has potentially a strong historical component. Convergence, on the other hand, points towards adaptive constraint in which the historical dimension is relatively unimportant.

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