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Evolution and Protein Folds

David J. States states at ibc.wustl.edu
Tue Jul 5 08:37:35 EST 1994


Ram Samudrala (ram at mbisgi.umd.edu) wrote:
: This is why I initially asked if there was any model that talked about
: evolution in terms of protein structure.  ... but I wanted models that
: would describe the probability of a function/structure arising in the
: first place!  Even if you use the random mutation mechanism, there
: must be a mathematical model (more complicated than a naive one),...

The fundamental point people miss in probability of evolution arguements
is separability in the problem.  The chances of AB evolving de novo as
a functional unit may be very different from the chances of A and B
evolving independently and coming together.  We know such events occur
biologically (kinase+Ig->PDGF receptor, kringles+serine protease -> TPA,
innumerable transcription factore examples, ...).  There is even evidence
that what we currently think of as domains may have arisen through
aggregation.  For example, there is an old paper (JMB ~1976) by Alan 
McClachlan identifying a 2-fold axis in the serine proteases and asserting
that they arose by duplication of a primordial domain.

Is there sufficient time/mutations in evolution for a novel small
domain (e.g. zinc finger) to have arisen by chance alone?  Sure.
Especially when you consider the extent of sequence variation allowed
within functional copies.

: --Ram
: ram at elan1.carb.nist.gov

David States
Institute for Biomedical Computing / Washington University in St. Louis
Subject: Re: Evolution and Protein Folds
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Ram Samudrala (ram at mbisgi.umd.edu) wrote:
: This is why I initially asked if there was any model that talked about
: evolution in terms of protein structure.  ... but I wanted models that
: would describe the probability of a function/structure arising in the
: first place!  Even if you use the random mutation mechanism, there
: must be a mathematical model (more complicated than a naive one),...

The fundamental point people miss in probability of evolution arguements
is separability in the problem.  The chances of AB evolving de novo as
a functional unit may be very different from the chances of A and B
evolving independently and coming together.  We know such events occur
biologically (kinase+Ig->PDGF receptor, kringles+serine protease -> TPA,
innumerable transcription factor examples, ...).  There is even evidence
that what we currently think of as domains may have arisen through
aggregation.  For example, there is an old paper (JMB ~1976) by Alan 
McLachlan identifying a 2-fold axis in the serine proteases and asserting
that they arose by duplication of a primordial domain.  Wally Gilbert
has made similar claims for the globins.

Is there sufficient time/mutations in evolution for a novel small
domain (e.g. zinc finger) to have arisen by chance alone?  Sure.
Especially when you consider the extent of sequence variation allowed
within functional domains.  Example: suppose a 32 amino acid domain has
4 sites where only a single amino acid is allowed, another 4 sites
where one of 2 are required, 4 sites where one of 4 are required, and
for the remainder, half of the amino acids can be substituted.  Odds of
an acceptable sequence arising by chance are one in (20*10*5)**4 * 2**20,
or about one in 10**18.  Still seems like a big number, but compared to
the numbers of progeny produced by a liter of culture infected with 
bacteriophage, not all that big.

: --Ram
: ram at elan1.carb.nist.gov

David States
Institute for Biomedical Computing / Washington University in St. Louis



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