BIBLE/ORIGINS - How frequent are usable proteins in sequence space?

From: Peter Ruest (
Date: Thu Feb 13 2003 - 00:52:31 EST

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    Dear friends,

    there has been quite some discussion recently about the origin of
    biological information, which I greatly enjoyed (Don Winterstein, Jim
    Armstrong, Blake Nelson, Robert Schneider, David Campbell,..). The
    question was how evolution of complex biological systems can happen, and
    whether God might be feeding in information, e.g. by selecting specific
    outcomes from apparently random distributions of mutations (perhaps by
    directing elementary events through specific "collapses" of
    quantum-mechanical probability density functions), or whether he is
    usually just watching what is happening "spontaneously" (apart from a
    difficult-to-describe general providential "maintenance" and holding in
    existence all that occurs), as his creation is fully functional.

    I have argued for "God's hidden options" of, e.g., selecting critical
    mutations from apparently random distributions: P. Rüst, "Creative
    providence in biology", PSCF 53/3 (Sept. 2001), 179-183;; P. Rüst, "God's
    Sovereignty in Creation - a reply to Howard Van Till", PSCF 54/3 (Sept.
    2002), 216-217.

    Now, I came across a very interesting paper by Denton M.J., Marshall
    C.J., Legge M., "The protein folds as Platonic forms: new support for
    the pre-darwinian conception of evolution by natural law", Journal of
    Theoretical Biology 219 (2002), 325-342. It's the Mike Denton who wrote
    the book, "Evolution, a Theory in Crisis". I met him in 1988 at the
    Conference "Sources of Information Content in DNA" in Tacoma, WA. At
    least at that time, he apparently was an agnostic. I haven't been in
    contact with him since. Despite his severe criticism of the evolutionary
    theory, he believed (and believes) that evolution is happening.

    Now, Denton and his coworkers propose that, for the origin of life and
    later, finding functional proteins should not be that difficult. The
    number of different protein folds is estimated to be about 1000 (or at
    most a few thousand). Despite the transastronomical size of protein
    sequence space, many of the folds are found again and again, e.g. the
    TIM (triosephosphate isomerase) barrel. Active sites of different
    functionality are attached at various places to the basic barrel or
    other scaffold. Denton and his coworkers propose that foldable protein
    sequences must be relatively common in sequence space, possibly even
    amounting to 1%, these folds being "determined by natural law, not
    natural selection": they are "lawful forms". The authors confirm that
    "selection must have a detectable proto-function to start with...
    _before_ selection begins there must be at least some sort of stable
    scaffold on which a function can be hung." But they suggest that because
    the association of many proteins with their prosthetic groups is
    basically spontaneous, "this raises the possibility that many protein
    functions may also have been generated deterministically in the
    protocell without the necessity for selection."

    I don't particularly care about Denton's Platonic-like idea, but I am
    intrigued with the question of the frequency, in sequence space, of
    proteins usable to initiate the evolution of a novel functional protein
    under the influence of natural selection - in a purely naturalistic
    setting, without divine guidance. I wonder what you think about Denton
    et al.'s proposal. Are their arguments for "relatively common" origins
    of useful proteins from random polypeptide sequences convincing? (cf.
    particularly the section "_per saltum_" on p.336 of their paper).

    In support of their claim, they adduce the following findings (of
    others): in libraries of random amino acid sequences, alpha helical
    proteins displaying cooperative thermal denaturation and specific
    oligomeric states have been recovered at frequencies of 1%; different
    structures may be adopted by the same sequence, such as prion proteins,
    or the Arc repressor mutant acting like a switch; the existence of
    overlapping genes. To me, these still look rather like indirect hints.
    But I haven't yet looked at the papers they refer to: Finkelstein &
    Ptitsyn 1987, Finkelstein 1994, Finkelstein et al. 1995, Cordes et al.
    1996, Sauer 1996, Plaxco et al. 1998, Brandon & Tooze 1999. In any case,
    it will not be easy to test population densities in a transastronomical
    sequence space! ;-)

    The experiments of Axe D.D., "Extreme functional sensitivity to
    conservative amino acid changes on enzyme exteriors", Journal of
    Molecular Biology 301 (2000), 585-595, suggest that functional enzymes
    (and thus, presumably, the few thousand biological folds) are extremely
    rare in sequence space:

    "Mutagenesis studies and alignments of homologous sequences have
    demonstrated that protein function typically is compatible with a
    variety of amino-acid residues at most exterior non-active-site
    positions. These observations have led to the current view that
    functional constraints on sequence are minimal at these positions. Here,
    it is shown that this inference assumes that the set of acceptable
    residues at each position is independent of the overall sequence
    context. Two approaches are used to test this assumption. First, highly
    conservative replacements of exterior residues, none of which would
    cause significant functional disruption alone, are combined until
    roughly one in five have been changed. This is found to cause complete
    loss of function in vivo for two unrelated monomeric enzymes: barnase (a
    bacterial RNase) and TEM-1 [beta]-lactamase. Second, a set of hybrid
    sequences is constructed from the 50%-identical TEM-1 and Proteus
    mirabilis [beta]-lactamases. These hybrids match the TEM-1 sequence
    except for a region at the C-terminal end, where they are random
    composites of the two parents. All of these hybrids are biologically
    inactive. In both experiments, complete loss of activity demonstrates
    the importance of sequence context in determining whether substitutions
    are functionally acceptable. Contrary to the prevalent view, then,
    enzyme function places severe constraints on residue identities at
    positions showing evolutionary variability, and at exterior
    non-active-site positions, in particular. Homologues sharing less than
    about two-thirds sequence identity should probably be viewed as distinct
    designs with their own sets of optimizing features."


    Dr. Peter Ruest, CH-3148 Lanzenhaeusern, Switzerland
    <> - Biochemistry - Creation and evolution
    "..the work which God created to evolve it" (Genesis 2:3)

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