Re: What is legitimate about the ID bait and switch scam at this time?

On 6/17/2025 10:07 AM, LDagget wrote:

On Mon, 16 Jun 2025 23:23:28 +0000, RonO wrote:
 

On 6/16/2025 5:39 PM, RonO wrote:

On 6/16/2025 2:25 PM, LDagget wrote:

On Mon, 16 Jun 2025 16:06:20 +0000, RonO wrote:
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On 6/15/2025 6:57 PM, MarkE wrote:

...
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I have never believed that chirality has ever been an issue for biology,
or my religious beliefs.  There is no reason to think that it ever was
an issue for biological evolution.  Life uses L amino acids to make
proteins, but they are only the proteins that were created after there
was a genetic code.  The peptidase in ribosomal RNA chose L amino acids
as the ones that it could join together into a polymer.  D amino acids
do not work for that peptidase.

>
Stop. That's bad biochemistry. Peptidyl transferase activity within
the ribosome works just fine with D amino acids if they are attached
to aminoacylated tRNAs. Specificity for L over D amino acids occurs
at the step of Amino Acid + tRNA to AA-tRNA.
>
Please don't BS about such basic foundational biochemistry. It doesn't
help.
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Frankly, I never heard of that aspect of the peptidase.  I knew that the
ribosome could make mistakes and it resulted in defective proteins, but
that it was rare.  So it could use D amino acids, but not on any type of
equal basis.
>
Apparently the ribosome can make mistakes, but they occur very rarely
because the enzyme does discriminate between D and L due to position in
the A site.
>
https://pmc.ncbi.nlm.nih.gov/articles/PMC6393236/
>
Abstract:
During protein synthesis, ribosomes discriminate chirality of amino
acids and prevent incorporation of D-amino acids into nascent proteins
by slowing down the rate of peptide bond formation. Despite this
phenomenon being known for nearly forty years, no structures have ever
been reported that would explain the poor reactivity of D-amino acids.
Here we report a 3.7Å-resolution crystal structure of a bacterial
ribosome in complex with a D-aminoacyl-tRNA analog bound to the A site.
Although at this resolution we could not observe individual chemical
groups, we could unambiguously define the positions of the D-amino acid
side chain and the amino group based on chemical restraints. The
structure reveals that similarly to L-amino acids, the D-amino acid
binds the ribosome by inserting its side chain into the ribosomal A-site
cleft. This binding mode does not allow optimal nucleophilic attack of
the peptidyl-tRNA by the reactive α-amino group of a D-amino acid. Also,
our structure suggests that the D-amino acid cannot participate in
hydrogen-bonding with the P-site tRNA that is required for the efficient
proton transfer during peptide bond formation. Overall, our work
provides the first mechanistic insight into the ancient mechanism that
helps living cells ensure the stereochemistry of protein synthesis.
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Apparently for the ribosomal peptidase to function optimally you need an
L amino acid attached to the tRNA.
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I am not going to bother to look up more research on the topic, but
Google claims that it is some of the aminoacyl-tRNA synthetases that
make the mistake and charge the tRNAs with the D amino acids, and that
there are chiral proofreading enzymes that help detect that issue. tRNAs
charged with D amino acids mess up ribosomal function.
>
QUOTE from Google:
1. The Role of aaRS and Chiral Proofreading:
Aminoacyl-tRNA synthetases (aaRS) are the enzymes responsible for
attaching the correct amino acid to its corresponding tRNA molecule in a
process called aminoacylation.
>
While aaRS generally exhibit high specificity for L-amino acids, some
are not perfectly enantioselective and can, to a limited extent,
mischarge tRNAs with D-amino acids.
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D-aminoacyl-tRNA deacylase (DTD) is an enzyme that acts as a "chiral
proofreader" to prevent the incorporation of D-amino acids into
proteins. It removes D-amino acids that have been incorrectly attached
to tRNAs.
>
2. Consequences of D-aminoacylated tRNAs:
Protein Synthesis Disruption: Ribosomes are primarily designed to
utilize L-amino acids during protein synthesis. Incorporation of D-amino
acids into proteins can lead to misfolding and degradation due to
geometric constraints within the polypeptide chain.
>
Translation Arrest: Studies have shown that even if a D-aa-tRNA is
delivered to the ribosome, it can disrupt translation. The presence of a
D-amino acid at the C-terminus of the nascent peptide can impede the
proper functioning of the peptidyl-transferase center (PTC), potentially
leading to translation arrest.
>
3. Role of DTD in Maintaining Protein Homochirality:
DTD plays a crucial role in maintaining protein homochirality (the
predominance of L-amino acids in proteins).
>
By efficiently removing D-amino acids from tRNAs, DTD helps prevent the
errors in protein synthesis that can arise from D-amino acid
incorporation.
>
4. Implications for Understanding Disease:
The ability of some aaRS to mischarge tRNAs with D-amino acids, coupled
with potential issues in DTD activity, suggests a possible link between
D-amino acid incorporation and certain disease states, particularly
neurodegenerative disorders.
END QUOTE:
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You are likely correct about the peptidase reactive center can
polymerize D and L amino acids, but you have to get them into the
correct position to make that peptide bond.  D amino acids are not held
in the correct position for the peptidase to work effectively.
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Ron Okimoto
>

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One neat thing that I found out while looking this junk up was that
ribozymes (RNA enzymes) have been created that have specific tRNA
acylation activity.  They can make ribozyme synthetases that use D or L
amino acids.
>
For any genetic code evolution scenario (except special creation) you
have to evolve the genetic code without having the extant protein
acyltransferases (before the code existed you could not make specific
protein sequences).  This means that when the genetic code was evolving
you needed mRNA, tRNA and acyltransferases to charge the specific tRNAs
with amino acids.  They have created RNAs that can charge specific tRNAs
with either D or L amino acids (one or the other stereo specific).  They
can even get them to charge tRNAs with a different amino acid or even a
novel amino acids that isn't used in normal protein synthesis.  This
means that the RNA world definitely could have evolved the genetic code.
  RNA could have been the genetic material, it would have been able to
make tRNAs and mRNAs, ribosomal RNA and aminoacyl transferases to get
the whole system up and running.
>
One open access paper:
https://www.nature.com/articles/nprot.2011.331
>
Ron Okimoto

 A few things.  The discrimination between L and D amino acids within a
Ribosome's peptidyl transferase is one of speed. For large bulky
side chains like Tyrosine, polymerization with a D-Tyr-tRNA is about
25 times slower than with the L form. But it still works. With smaller
side chains, the discrimination is less which is highly suggestive of
a "something in the way" active site. Variant ribosomes that do not
discriminate against D amino acids have been developed for in vitro
ribosomal synthesis.

What I have always gone by was that when D and L charged tRNAs were in the mix, translation still proceeded, but more slowly and L amino acids were still used in making the peptide.  I did not recall any type of controversy involved, but the paper that I linked to noted that it has never been understood why the D amino acids were not incorporated. Apparently the ribozyme peptidase in the ribosome can polymerize both D and L amino acids, but the intact ribosomes can descriminate.  I also found out that work has been done to improve the ribozyme peptidase and they can make RNA sequence modifications that improve the peptidase activity, but it still polymerizes both D and L amino acids.  Going by what the paper claimed it looks like it takes longer to use D amino acids in the intact ribosome because if the R groups do go into the R group cleft the reactive parts of the amino acid are not in the proper position for the peptidase to work.  The D amino acid charged tRNA has to wait until the amino acid R group wiggles out of the cleft and into a position where a peptide bond can form.  Apparently, the D charged tRNA must leave the A site before that happens most of the time.

 AA tRNA transferases are the main point of chiral discrimination. As
a general rule, the ribosome doesn't "know" if an AA-tRNA is loaded
with an AA that is miss-matched to the anti-codon.
 Simplified models for the evolution of ribosomes consider the basic
chemistry of amino acylation as a means of activating the Carboxyl
of an amino acid for attack by the amino group of another. This is
a very common reaction from simple organic chemistry. Such a simple
chemical mechanism implies a pathway from general non specific
amino acid polymerization, to increasing specificity. The specificity
could plausibly arise in the following way.
Primative. Amino acids activated at C side with single nucleotides
via simple ribozymes.
2 small nucleotide polymers are used in place of single nucleotides,
leveraging the advantage of better substrate binding afforded by
RNA::RNA interactions.
3 the condensation step linking one acylated AA to another is catalyzed
by a ribozyme that binds two acylated AA nucleotide polymers
(progenitors of tRNAs before anticodons) in proximity. Catalytically,
this is essentially an entropy reduction that simply traps a pair
of reactants in close proximity in analogy with many surface catalysts.
This can achieve a very large increase in reaction speed without
requiring a precise active site as the fundamental condensation reaction
already has a relatively low activation barrier.
4 peptide sequence specificity (small polymers) can arise with 2
independent developments. First, the ribozymes that acylate amino
acids diverge to have discriminatory affinities for different amino
acids. This can be simple class discrimination at first, big or
small, hydrophobic or hydrophilic, up to single AA specificity.
At the same time, the associated tails of RNA polymer beyond the
reactive nucleotide can diverge in co-evolution with the acylating
ribozyme. This isn't a hopeful monster, it's more of a try to stop
such things from diverging (you can't).
 The pathway continues to write itself along similar lines of
changes that are inevitable. The advantages for synthesis of small
somewhat specific peptides would include the functional features
that arise from small amphipathic peptides in areas like membrane
stabilization, co-factor expansion of ribozyme functionality and
ribozyme stablization, and metal chelation.
 As small peptide utility increases with co-dependence of ribozymes,
the value of higher fidelity synthesis increases to drive specificity
in amino acylation of more specific proto-tRNAs. Compartmentalized
function (ur-tRNA binding vs AA binding) would permit mixing and
matching of some ribozymes for cassette style evolution that could
spread advancements from on family of AA - tRNA symthetases to
others via RNA recombination/splicing reactions.
 Yes, there are myriad ways to go wrong along the way. When things
go wrong, that lineage dies. The ability to go wrong is not the
error catastrophe a certain mathematician used to assert it would
be.
 The big move is the recruitment of an external templating molecule
to serve to stage a sequence of ur-tRNAs. This would be a proto
mRNA.
 

I just wanted to note that the fact that ribozyme synthases exist, means that the RNA world could have evolved the genetic code.
My guess is that acylation of RNAs started as a means of keeping valuable amino acids at higher concentrations inside of the cell.  The activation of the amino acid for peptide bond formation was sort of a bonus.  You need amino acids to make more nucleotides, and the first peptides made with acylated RNA were likely used for amino acid storage.   The genetic code may have first evolved to make peptides composed of the most useful amino acids for the existing cellular metabolism.  Once the peptides started to have useful functions on their own the genetic code would have been expanded to include the current group.  It allows selection to be involved in creating the first code (the initial "code" template may have been part of the peptidase ribozyme when only a few amino acids were needed to be stored, and mRNA would evolve with an expanding number of amino acids being used) and then further selection to evolve a more useful 3 nucleotide code.
How this relates to selection of L amino acids is that, at this time, L amino acids are used to make nucleotides, and they would have been the ones that the first Ribozymes would want to make more of and to keep and store inside the cell.  I just assume that the current system was conserved, and proteins replaced the original nucleotide making machinery and conserved the use of L amino acids because all the replacements had to work within the existing system as the replacement proteins evolved.
Ron Okimoto