Despite the diversity of protein superfamilies, sequence space is extremely sparsely populated by functional proteins. Most random protein sequences have no fold or function.
Enzyme superfamilies, therefore, exist as tiny clusters of active proteins in a vast empty space of non-functional sequence. The density of functional proteins in sequence space, and the proximity of different functions to one another is a key determinant in understanding
evolvability. The degree of interpenetration of two
neutral networks of different
activities in sequence space will determine how easy it is to evolve from one activity to another. The more overlap between different activities in sequence space, the more
cryptic variation for
promiscuous activity will be. Protein sequence space has been compared to the
Library of Babel, a theoretical library containing all possible books that are 410 pages long. In the
Library of Babel, finding any book that made sense was impossible due to the sheer number and lack of order. The same would be true of protein sequences if it were not for natural selection, which has selected out only protein sequences that make sense. Additionally, each protein sequences is surrounded by a set of neighbours (point mutants) that are likely to have at least some function. On the other hand, the effective "alphabet" of the sequence space may in fact be quite small, reducing the useful number of amino acids from 20 to a much lower number. For example, in an extremely simplified view, all amino acids can be sorted into two classes (hydrophobic/polar) by
hydrophobicity and still allow many common structures to show up. Early life on Earth may have only four or five types of amino acids to work with, and researches have shown that functional proteins can be created from wild-type ones by a similar alphabet-reduction process. Reduced alphabets are also useful in
bioinformatics, as they provide an easy way of analyzing protein similarity. ==Exploration through directed evolution and rational design==