Protein folding fitness

Any theoretical study of applied molecular evolution needs information on the fitnesses of the molecules in the search space, as it is not possible to characterize the performance of search algorithms without knowing properties of the landscape being searched [63], Since the ideals of sequence-to-structure or sequence-to-function models are not yet possible, it is necessary to use approximations to these relationships or make assumptions about their functional form. To this end, a large variety of models have been developed, ranging from randomly choosing affinities from a probability distribution to detailed biophysical descriptions of sequence-structure prediction. These models are often used to study protein folding, the immune system and molecular evolution (the study of macromolecule evolution and the reconstruction of evolutionary histories), but they can also be used to study applied molecular evolution [4,39,53,64-67], A number ofthese models are reviewed below. 

A protein as a three-dimensional jig-saw puzzle its sidechains fit together snugly, excluding water. (3) The pathway by which proteins fold spontaneously. (4) Flexibilities of conformations. (5) Interactions with small molecules, other proteins, and other macromolecules. 

Another approach is to map the arrangement of secondary structural elements onto the known tertiary structures of other proteins. Currently, approximately one hundred unique protein folds have been identified. There is some question as to if this is an upper limit. If this is indeed the case, then the protein of unknown structure must adopt a known topological fold. The secondary structural elements are mapped onto the template of the different known protein structures. The best fits, as judged by the environmental factors (solvent accessibility) of the individual amino acids, are then further analyzed as probable folds. This procedure is referred to as threading the secondary elements into three-dimensional structures [28],... 

One advantage is that the template and test protein do not need to be of similar lengths. A very good fit could be identified for the N-terminal portion of a very long test sequence by a much shorter template Large proteins often adopt different structural domains with identifiable folds. Likewise, a short test sequence could adopt a fold that utilizes only a small portion of the template. This rather straightforward sounding method avoids the problems associated with the identification of secondary structure elements. The assumptions are that most protein folds have already been identified and therefore the unknown structure of the test protein will most likely resemble a fold within the database. It is clear that a novel protein fold will not be identified by this method. 

Rost, B. Fitting 1-D predictions itno 3-D structures , in Protein Folds, A distance-based approach , Bohr, H., Brunak, S., Eds., CRC Press, 1996, pp. 132-151. 

Protein-based life as an emergent property of matter the nature and biological fitness of the protein folds Michael J. Denton... 

Another general feature of the protein folds that confers an important element of fitness is that they generally contain a relatively compact hydrophobic core. This provides a convenient reaction chamber for organic syntheses that are, for the most part, difficult to carry out unless water is excluded. The dense hydrophobic core may also confer on many folds the ability to stack together into various stable supramolecular assemblies that form the basic elements of the cytoskeleton nucleosomes, cytoplasmic filaments, microtubules, and so forth. 

Considerating the number and relative stringency of the functional criteria satisfied by the protein folds - - self-organizing robustness in conjunction with marginal stabihty, diverse architectures, a hydrophobic core fit for organic synthesis, diverse bulk properties, etc. - it seems likely that few other types of polymer will be equally fit. At present, I think that current knowledge is consistent with the possibility that the protein folds represent an ensemble of natural forms uniquely fit for the mechanism we call life. If correct, this not only would support Henderson s contention that the cosmos is fine-tuned for carbon-based life, but would further restrict this statement to the protein-based variety of life that exists currently on earth. 

The protein-only hypothesis indicates that the scrapie form of the prion protein can promote the conversion of the cellular form. This leads to the conclusion that prions themselves can act as chaperones (Liautard, 1991). Thermokinetic analysis of protein folding shows that a misfolded chaperone gives rise to new misfolded chaperones, which fit very well to the protein-only hypothesis in which PrP triggers the formation of PrP. ... 

The mysterious behaviour of bio-macromolecules is one of the outstanding problems of molecular biology. The folding of proteins and the replication of DNA transcend all classical mechanisms. At this stage, non-local interaction within such holistic molecules appears as the only reasonable explanation of these phenomena. It is important to note that, whereas proteins are made up of many partially holistic amino-acid units, DNA consists of essentially two complementary strands. Nonlocal interaction in DNA is therefore seen as more prominent, than for proteins. Non-local effects in proteins are sufficient to ensure concerted response to the polarity and pH of suspension media, and hence to direct tertiary folding. The induced fit of substrates to catalytic enzymes could be promoted in the same way. Future analysis of enzyme catalysis, allosteric effects and protein folding should therefore be, more ambitiously, based on an understanding of molecular shape as a quantum potential response. The function of DNA depends even more critically on non-local effects. 

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