Re: Evolution of proteins in sequence space

From: bivalve (
Date: Thu Aug 02 2001 - 13:49:59 EDT

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    It's good to see more realistic estimates of probability. A few considerations that will affect the calculations:

    PR>Basically, any sequence within the transastronomically huge combinatorial space of the L^20 possible sequences of proteins of length L would be accessible during evolution, if there is a mutational path which leads from an existing sequence to the target considered and which does not contain any intermediates which are selected against (or even lethal). <

    DC: Do we have any idea of the relative proportions of theoretically useful versus non-useful proteins that are inaccessible due to these reasons?

    PR>As the human genome contains an estimated 30,000 genes, and the number of different protein folds is estimated to be a few thousand, we may, as a very rough approximation, assume that there are less than 10^4 basically different protein families in the biosphere, within each of which a number of similar proteins can be derived from each other by feasible evolutionary paths. <

    DC: Are there other theoretical biospheres using a different set of basic proteins?

    PR>These estimates assume that directed evolution in the lab is a valid model for natural evolution. Of course, this is not the case, as in directed evolution one does not have to bother about the viability of each intermediate organism in a linear sequence of point mutations, but only about the isolated activity of a new protein sequence after several or many mutations. Directed evolution jumps around in sequence space, whereas natural evolution is limited to single-step paths, and none of these steps must go downhill on the fitness surface. <

    DC: On the other hand, the directed evolution in the lab started from a random set of proteins, whereas evolution of a new protein sequence from an existing sequence starts with an already functional protein, from which basic structural units can be retained. This relates closely to the question of how easy it is to produce a protein of a different family via mutation. If it is not that difficult, then an enormous number of starting points are feasible.
    Note also that small decreases in fitness, and sometimes large ones, may still be viable. The level of selective pressure will determine how far downhill each step may be without being eliminated by selection.

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