Protein molecular evolution space

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. 

It is in the realm of very large combinatorial libraries that selection rather than screening gains crucial importance. As the focus shifts from randomizing an eight-residue peptide to a 100 amino acid protein (the typical size of a small functional domain, for example a chorismate mutase domain), the number of sequence permutations rises to an astronomical 20100. The ability to assay even a tiny fraction of this sequence space in directed molecular evolution experiments demands selection, even though initial development of an appropriate system may be considerably more involved than the setup of a screening procedure. 

As outlined above the chemical structure space accessible to small drug-like molecules is so vast that it cannot be covered by chemical synthesis in a comprehensive and meaningful manner. During evolution nature herself has explored only a tiny fraction of chemical space in the biosynthesis of low molecular weight natural products. The same is true for the evolution of the targets bound and modulated by natural products, for example proteins. It has been estimated that during the evolution of a protein consisting of about 100 amino acids only a tiny fraction of all amino acid combinations could have been biosynthesized. However, in protein evolution, structure is even more conserved than the sequence since similar structures can be formed by very different sequences. Thus the protein structure space explored by nature is limited in size. ... 

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