Thank you for taking the time to send me the color article and for giving me
your explanation. It is quite clear now to me what the chemical processes are
in this molecular self-replication.
I am aware of the strong scientific arguments for common ancestors between
different species; however, I have doubts that chance and natural forces such
as natural selection can completely explain the origin of all life. After
reading your article there are some challenging question that I still
perceive. I was going to list them in a discussion group; however, I thought
I send them to you first in case you wanted to comment on them and if you
donât mind I could also post your comments. However, if you do not prefer
this, that is fine with me, just inform me and I wonât post them. This field
is not my specialty so obviously there may be solutions that I am not aware
of, so it is best to get comments from the experts.
As you probably suspect I have an interest if there is an intelligence that
had a plan with humans in mind. It is true, I am interested if it can be
rationally shown that there is evidence that an intelligence had a plan with
humans in mind. Investigating if natural process can explain the origin of
life is the way to determine whether or not an intelligence was required to
create life.
Below are list what I perceive as three challenging issues for abiogenesis.
1) Self-Replication of 3-D shape
I think that the 3-D shape of biological molecules is crucial for the
molecules to perform certain chemical reaction because the 3-D shape forms
tunnels, cavities or grooves that are suited for holding other molecules in
place long enough to cause certain important reactions to occur. The backbone
of the self-replicating peptide according to the Figure 1 of your paper (Ref.
1) has what appears to be an essentially 1-D straight shape. It appears to me
this is what allows it to self-replicate. Since it remains straighten out
then the bonds that form during the complementary pairing are accessible
allowing the new molecule to assemble on the old to form a new replicate. It
appears to me that moving beyond this 1-D shape produces fundamental
difficulties.
Ref. 2 which also discovered a self-replicating molecule explains this
problem, "The chain was so long and flexible that the self-replicating
structure doubled over on itself, rather like a jackknife folding shut." In
this case the folded over molecule could not self-replicate They solved this
problem by straightening out the molecule. "The remedy called for inserting a
larger and more rigid molecule in place of the single chain to prevent
folding. Our choice was a larger stacking surface, a napthalene, bolstered by
a less flexible link between the two components, a cyclic ribose group".
I think that polymers with a 3-D folded up backbone could not self-replicate
for the following reasons: 1) The 3-D structure does not have geometrical
properties that would allow it to act as a template off which a replication
of itself could form because the some of the chain would not be accessible to
forming the complementary pairing relationships. 2) Many of the angles are to
tight and the density of the molecule so great that an attempt at replication
would cause interference problems know to chemist as steric effects. 3) If a
self replicator did form it could not get out because it would be all tangle
up in this 3-D structure. Thus, it would have to break up in order to get out
then it would not be a replication anymore.
Key functions in a DNA based cell appear to definitely require large 3-D
molecules such as polymerase for DNA transcription and ribosome for protein
formation. In any plausible origin of life scenario eventually 3-D
replicating molecules will have to form, but when they initially form it
seems they couldn't self-replicate on an individual basis so there will have
to be already some more complex system in place to replicate them. This
system would have to at least unfold the molecule and hold it into a position
that would allow for replication of the folded molecule. This system I
suspect would have to include 3-D molecules. These 3-D molecules would also
have to self-replicate; thus, additional 3-D molecules would be required for
their self-replication. Thus, there would have to be a system of
interdependent 3-D molecules that compliment each other to function as a
whole to self replicate.
Since these molecules have to compliment each other they must have the right
sequence that performs the right function. Ref. 3 shows that out of all
possible 110 site amino acid sequences for the cytochrome c protein 2.3x10^93
of them are functionally equivalent which represent a very small fraction
(2.00x10^-44) of the total 1.15x10^137. The chance of getting two molecules
with the right functions is the multiplication the chances of getting the
individual molecules. Thus, Ref. 3 concludes, "Since the probability of a
mutational event is a number much smaller than unity, simultaneous events are
of the second order". Since the scenario being considered is the evolution of
the first replicator involving 3-D molecules; there is no basis for natural
selection to help select out the fitter 3-D molecules. Thus, it appears
difficult to avoid these small probabilities that imply the natural
development of 3-D replicator as plausible. This difficulty is further
emphasized by estimates of the minimum number of proteins of molecular
functions required for a minimum self-replicating cell. Ref. 3 reports an
estimate of at least 300 proteins.
The combination of your result for self-replication of individual molecules
and Ref. 1 appears to emphasize that self-replicating molecules cannot have a
folded over backbone; thus, they must be straight. Does you self-replicating
peptide provide insight into a solution to this problem? Do you have other
references or theories that you can point to that provide plausible solutions
to this problem?
2) Side Reactions
I think that in the prebiotic soup there would be a milieu of molecules that
could get involved with candidates for replication. These molecules would
produce side reaction which could greatly reduce the efficiency of the
replication making it quite implausible for the replication process to
continue to grow more replicators. You mentioned in your article that the
reaction was made up of an equal mixture of the electrophilic fragment and
the nucleophilic fragment. Was the reaction made up of just these fragments?
If yes, it appears to me that this does not represent a realistic prebiotic
soup. If a more realistic concentration and mix of molecules were run do you
think that sufficiently efficient self-replication of this peptide would
occur?
3) Stereochemistry
Constant sterochemistry along a chain causes a constant placement of
molecules on one side of the chain so that the complementary pairing
relationships can be formed on one side. If along the chain the
stereochemistry switched, the new molecule trying to form the pairing
relationships would have to wrap around which would require extra length so
it would not be a replication. Thus, constant sterochemistry has fundamental
value in allowing replication to occur. Did the amino acids that made up this
peptide all have the same handeness or stereochemistry? If no, then what do
you think caused the right molecules to line up on one side so that the
proper complementary pairing relationships could be made?
References
1. David H. Lee, Juan R. Granja, Jose A. Martinez, Kay Severin, M. Reza
Ghadiri, A Self-Replicating Peptide, Nature, Vol. 382, 8/8/1996
2. Rebek, J., Synthetic Self-Replicating Molecules, Scientific America, July
1994
3. Yockey, Information Theory and Molecular Biology, Cambridge
>SELF-REPLICATION: Even peptides do it
>
>By Stuart A. Kauffman
>
>This article originally appeared in Nature 382
>August 8, 1996.
>Copyright 1996 by Nature.
>
>On page 525 of this issue [1], David Lee and colleagues describe what
>appears to be the first case of a self-replicating
>peptide, a result that may prove to be either a mere chemical curiosity,
>or seminal.
>
>The authors show that a 32-amino-acid peptide, folded into an alpha-helix
>and having a structure based on a region of
>the yeast transcription factor GCN4, can autocatalyse its own synthesis by
>accelerating the amino-bond condensation of
>15- and 17-amino-acid fragments in solution (see Fig. 1 on page 525).
>
>The design of this replicator was based on a protein found in nature, an
>alpha-helical coiled coil. Reasoning that a given
>alpha-helical subunit of the entire structure could be seen as a
>complementary binding surface, acting cooperatively to
>organize other participating peptide subunits in the coiling, the authors
>hoped that a similar 'template' function could be
>found in smaller fragments. The ligation, or joining, site was constructed
>so as to lie on the solvent-exposed surface of
>the alpha-helical structure of their 32-amino-acid sequence.
>
>Lee et al. established autocatalysis by showing that by increasing initial
>concentrations of the 32-amino-acid template,
>with constant concentrations of the 15- and 17-amino-acid substrates, a
>marked increase was produced in the initial
>rates of template production. The increase correlates with the square root
>of the initial template concentration, as seen in
>self-ligating polynucleotide systems [2,3]. The reaction is region- and
>chemically selective, yielding less that 15% side
>products, and proceeds through the major autocatalytic pathway open to the
>system.
>
>Do these results reflect a rare chemical quirk in the repertoire of
>peptides and polypeptides, or might they hint at a route
>to self-reproducing molecular systems on a basis for wider than
>Watson-Crick base-pairing in polynucleotides? At this
>stage, we cannot know, but the way is now open to investigate.
>
>The first step, beyond independent verification of the reaction system, is
>to construct self-reproducing cross-catalytic
>systems of two peptides, A and B, here A catalyses the formation of B from
>B's two fragment substrates, and B does
>the same for A. Such a system would be collectively autocatalytic--no
>molecule would catalyse its own formation, but
>the system would collectively catalyse its own formation from 'food'
>sources--where, the two A fragments and the
>two B fragments. If collectively autocatalytic peptide sets with two
>catalytic components can be constructed, can
>systems with three, four or hundreds of cross-coupled catalysts be
>created?
>
>Such experiments are important. A free-living cell, prokaryote or
>eukaryote, is in fact a collectively autocatalytic
>system--virtually no molecule, including DNA, catalyses its own formation.
>Most of the cell's catalysts are proteins, so
>if collective autocatalysis in complex peptide systems is possible, we
>would have a new model for self-reproducing
>systems.
>
>A host of experimental and theoretical questions about such systems
>present themselves. If such systems can be
>created, is it possible in general to constrain the side reactions enough
>for the autocatalytic system to increase in
>concentration as the fragment 'fuel' is added? Would such an increase be
>aided by confining reactions to a surface, or
>within a small volume? Are there means other than thioester promotion to
>drive the synthesis of peptide bonds? Even if
>such systems can be designed using clever synthetic chemistry, is the
>spontaneous formation of collective autocatalytic
>sets of peptides rare or common as a function of the diversity of the
>peptides, and of the regions of sequence space they
>are derived from? Can such autocatalytic systems be constructed or
>spontaneously assembled from mixed polymer
>systems consisting of DNA, RNA, peptides and perhaps other polymers and
>their building blocks? Can such systems
>evolve to 'neighbouring' autocatalytic systems while retaining 'catalytic
>closure', and could current life have evolved
>from one?
>
>The new autocatalytic ligation-reaction system is merely exergonic: left
>to its own devices, the system will simply run
>to equilibrium. Can an autocatalytic system be created that carries out
>thermodynamic work cycles whereby the system
>sustains displacement from equilibrium, performs coordinated work and
>achieves such coordination by controlling,
>constraining and 'correcting' unwanted side reactions (as in DNA editing
>and repair; P. W. Anderson, personal
>communication and ref. 4) to enhance its own rate of reproduction?
>
>The dominant view of life assumes that self-replication must be based on
>something akin to Watson-Crick base pairing.
>The 'RNA world' model of the origins of life conforms to this view. But
>years of careful effort to find an enzyme-free
>polynucleotide system able to undergo replication cycles by sequentially
>and correctly adding the proper nucleotide to
>the newly synthesized strand have not yet succeeded [5,6].
>
>A polynucleotide system based on a ribozyme polymerase able sequentially
>to add the correct nucleotides (and thus
>copy itself) might work. In contrast, the simple and successful
>reproducing molecular systems described by Lee et al.
>[1] and by von Kiedrowski [2] which uses a single-stranded DNA hexamer and
>its two trimer fragments) are based on
>a polymer catalysing its own formation from two fragments. Both show that
>autocatalytic systems based on specific
>ligation reactions are possible. Because a variety of polymers and small
>molecules can catalyse such reactions, these
>results may prove seminal: the creation or spontaneous formation of simple
>or collectively autocatalytic sets may occur
>far more readily than we thought. Given the emerging field of 'molecular
>diversity', with its capacity to synthesize
>high-diversity DNA, RNA and peptide libraries [7], these questions are now
>open to detailed scrutiny.
>
>References
>
>[1.] Lee, D. H., Granja, J. R., Martinez, J. A., Severin K., and Ghadiri,
>M. R. Nature 382 525-528 (1996). [return
>to text]
>
>[2.] von Kiedrowski, G. Agnew. Chem. 25 932-935 (1986).
>
>[3.] von Kiedrowski, G., Wiotzka, B., Hielbing, J., Matzan, M. and Jordan,
>S. Agnew, Chem. 30 423-426 (1991).
>
>[4.] Hopfield, J. J. Proc. Natl Acad. Sci. USA 71 4135-4139 (1974).
>
>[5.] Joyce, G. F., and Orgel, L. E. J. Mol. Biol. 188 433-437 (1986).
>
>[6.] Joyce, G. F. Cold Spring Harb. Symp. Quant. Biol. 52 (1987).
>
>[7.] Scott, J. K., and Smith, G. P. Science 249 386-389 (1990).