Re: There was never a moment in time when

Perplexed in Peoria <jimmenegay@xxxxxxxxxxxxx> wrote or quoted:
> "Tim Tyler" <tim@xxxxxxxxxxx> wrote in message news:d8kgsr$bjp$1@xxxxxxxxxxxxxxxxxxxxxx
> > Perplexed in Peoria <jimmenegay@xxxxxxxxxxxxx> wrote or quoted:

> > > The error correction mechanisms that exist in contemporary organisms
> > > are extremely complex, because they have to be complex in order to
> > > achieve "energy efficiency". But if energy efficiency is not a
> > > consideration, then there is a trivially simple mechanism for achieving
> > > arbitrarily low error rates. It is called "kinetic proofreading".
> > >
> > > The idea is simple. You have a "forward reaction" and a "reverse
> > > reaction". The forward reaction makes progress in whatever it is
> > > that you are doing - template directed polymerization of RNA, for
> > > example. The forward reaction may take place "correctly" (the
> > > right base gets added) or "incorrectly" (the wrong base gets added).
> > >
> > > The reverse reaction undoes progress. [...]
> >
> > That's precisely how crystal growth processes are so fantastically
> > accurate - they enjoy built-in error correction.
>
> I'm glad you responded, Tim, because I wanted to say that crystal growth
> is precisely NOT an example of kinetic proofreading. Yes, you have
> both a forward and a reverse reaction, in a sense, but in your case
> the forward and reverse reaction are exact reversals of each other.
> You don't expend energy in a futile cycle!
>
> In the case of kinetic proofreading, energy (high energy bonds) is
> dissipated in a "futile cycle" when you take one step forward followed
> by one step back. That is the magic ingredient in the process which
> allows unlimited amplification of marginal inherent accuracy.
>
> The accuracy of crystal growth is limited by Boltzman's formula. Those
> who worry about Eigen's paradox also calculate maximum RNA polymerization
> accuracies (without error correction) using Boltzman's formula. But,
> when kinetic proofreading is used, Boltzman's formula is no longer
> applicable (or rather, you get to throw some of that futile-cycle energy
> into the exponent, so the formula gives a different answer.)
>
> I realize that you frequently wax rhapsodic regarding the "error correcting"
> abilities of crystal growth, but you are wrong. The error correction
> that takes place in crystal growth is no different in kind from the error
> correction that takes place in any other sequential reversible process
> such as RNA folding, or the binding of enzyme and substrate. The accuracy
> is limited by Boltzman's formula. True proofreading, ie. "kinetic
> proofreading", is different. You should read Yarus's articles, or some
> other tutorial on the subject.
>
> Now it is not impossible that Cairns-Smith's hypothesis might be modified
> so that it too could make use of kinetic proofreading. But doing so
> eliminates much of the simplicity of the hypothesis - and frankly, the
> only thing the hypothesis has going for it is its simplicity. In order
> to get kinetic proofreading, you need for BOTH the forward and the reverse
> reactions to be "downhill" thermodynamically. Obviously, you can't get
> both reactions to be downhill simultaneously if your "monomers" are simple
> ions (unless you can think of a way to "activate" such ions). But you
> can get both reactions to be downhill sequentially, using something like
> Hendrick's environmentally forced cycles. I don't know if something like
> that could be made to work. Personally, I find the idea unattractive.

Phew! ;-)

After some reflection, I think you need to look again at crystal growth
processes.

Firstly, I can confirm crystal growth processes *really* *do* satisfy
your points in the previous post:

``Now, in order for kinetic proofreading to work you need the
following:

1. The forward reaction must be (on average) slightly faster
than the reverse reaction. This means that you make net
progress, even if there are nine steps back for every ten
steps forward. It is worth pointing out that you can tune
your reaction rates to the proper ratio either by tuning the
ribozymes, or by tuning the concentrations of activated
monomers.

2. The forward reaction is slightly inhibited when the
previously added base was incorrect. Notice that all this
requires (in the RNA polymerization case) is that the
forward reaction prefers to extend from a well-formed helix
rather than entending from an unpaired base.

3. The reverse reaction is slightly inhibited from acting
incorrectly - that is, from hydrolyzing a correct base.
Notice that all this requires is that the hydrolysis
mechanism works better when the helix is "denatured"
slightly at the growing end.

And that is all you need. [...]''

What about reversibility? It is true that crystal growth processes
tend to be reversible - as indeed do all microscopic reactions.

However the crystal growth processes under discussion are not *exactly*
reversible, and *do* wind up dissipating energy - on average.

To see why, consider one step "forward" and one step "backwards" -
which consists of one unit crysatallizing onto the surface and then
dissolving off again.

How is this process /not/ symmetrical and reversible?

The asymmetry lies in the degree of saturation of the surrounding liquid.
When the unit crystallizes, the chances are it did so because the
surrounding liquid had slightly more units in solution than could be
supported without precipitation. And when it dissolved, the chances are
that it did so because it was in a region that was slightly less
heavily saturated.

So: one forward cycle and one reverse cycle is likely to have had the side
effect of moving a unit from a point in the liquid where there were
slightly more units than usual to one where there were fewer free units -
i.e. energy is dissipated and the cycle is not reversibile (except in
the simple sense that all the laws of physics are thought to be
reversible).

If you are poetically inclined, you could invoke this dissipated energy as
"paying" for the resulting error correction process.

Regarding:

``In order to get kinetic proofreading, you need for BOTH the forward and
the reverse reactions to be "downhill" thermodynamically. Obviously,
you can't get both reactions to be downhill simultaneously if your
"monomers" are simple ions (unless you can think of a way to "activate"
such ions).''

The key idea here is that the two reactions are thermodynamically
downhill in the same *place* - but at slightly different *times*.

They do not *need* to both be downhill /simlutaneously/ - if both
forward and reverse reactions are thermodynamically favoured
repeatedly sequentially, that is sufficient.

That can happen in a liquid near super-saturation - if the degree
of saturation varies a bit from place to place - and that can happen
easily enough - simply through random thermal motion, or turbulent
fluid flow.

Somewhat delightfully for crystal error correction processes, the
very act of a unit crystallizing has the effect of decreasing the
level of super-saturation in the surrounding liquid locally -
increasing the probability of the reverse reaction happening
immediately.

Cairns-Smith understood all this. He goes into some depth about the
error correction exhibited naturally by crystal growth processes on
pages 155 of 159 of "Genetic Takeover" - repeatedly referring to the
effect as "proof reading". He also points out that such error
correction could be taken too far - balance the system precisely
enough on the "edge" of super-saturation and what you are likely
to get is a perfect crystal - one devoid of the fault structures
that could act as an information storage medium responsible for
inheritance.

Crystal growth processes really do exhibit such error correction
processes naturally - "out of the box", so to speak - and they
are one of the very few plausible pre-biotic systems to do so.

It's fundamentally the reason for their fantastically high fidelity -
which is hard to deny if you are ever faced with macroscopic crystals
on the scale of common quartz crystals.

I think you need to look again at crystal growth processes, bearing
what I've written here in mind.
--
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