Why protein folding permits "small changes" but prohibits macroevolution.

[lucaspa]

Of course we are told in evolutionary theory that evolution has no goal and that each step in the evolutionary step by step process must be an improvement so that natural selection can cause it to become more frequent in the population.

Two misconceptions:

1. Natural selection has no long-term goal. But it does have a short term goal: get the best available design for the particular environment.

2. It's not "improvement", but rather the variation must be beneficial in that particular environment.

So I fixed the Dawkins model in the following ways:

1) start with a sentence that makes sense,

2) assume that a letter is selected at random and modifies a randomly selected position in the current sentence,

3) examine the modified sentence to see if it not only makes sense, but makes more sense than the previous sentence did,

4) finally, see if the new sentence "fits" well into the paragraph, like the original sentence
did.

That's the strawman. What you have looked at is "purifying" or "stabilizing" selection. What you have is a "fitness peak". IOW, the design is already fit for that particular environment. So any variation will fit make the individual (sentence in this case) less fit.

BUT, if you change the environment so that you want a different sentence, then natural selection will eventually generate that new sentence.

In all lifeforms we know about, a string of DNA (nucleotides) called a gene is tranformed into another string, RNA, which in turn is used as a template to produce a string of amino acids, a protein. Proteins could be called the "building blocks" of life. They act as "frameworks", enzymes (e.g. hormones), and may play other roles as well.

Hormones are NOT enzymes! Geez, your knowledge of biochemistry is so poor, no wonder you make strawmen. An enzyme would be cytochrome c or sulfatase. Proteins also make up about 60% of the cell membrane, act as carriers for other molecules, and receptors (in the cell membrane) for lots of chemicals, including hormones. Proteins also act as transcription factors, either repressing genes so they are not turned into RNA, or activate genes so that they are transcribed to RNA.

The string of amino acids known as a protein typically fold up from their string form into a more compact "ball" form. Failure to do this usually means that the protein fails to do its job and is pretty much worthless.

There are several different shapes for proteins. Collagen type I, for instance, (in your bones, tendons, ligaments, and skin) is a tight helix formation. Other proteins, such as beta keratin, are sheets. A typical "ball" protein will have several "domains" with different shapes.

But changing a protein's shape does NOT make it worthless. Instead, it can simply give it another function. For instance, change 12 amino acids in human hemoglobin and you don't end up with a "worthless" protein, but you end up instead with a protein that would allow humans to stay many minutes underwater because it holds oxygen differently.

In one bacteria -- b subtilis -- change one amino acid and you allow the bacteria to germinate in an entirely different environment. In this case it is an environment of D-alanine. J Bacteriol 1999 Jun;181(11):3341-50. Isolation and characterization of mutations in Bacillus subtilis that allow spore germination in the novel germinant D-alanine. Paidhungat M, Setlow P

"To more definitely identify genes that encode germinant receptors, we isolated mutants whose spores germinated in the novel germinant D-alanine, because such mutants would likely contain gain-of-function mutations in genes that encoded preexisting germinant receptors. Three independent mutants were isolated, and in each case the mutant phenotype was shown to result from a single dominant mutation in the gerB operon."

In the case at hand most people would agree that changing letters one at a time in a sentence randomly would almost never generate a new sentence that made sense and also "fit" better in the paragraph it was embedded in.

Again, this is purifying selection (do a quick search on the web). You have set up a situation where the sentence "fit ... in the paragraph it was embedded". The paragraph is the environment. BUT, change the environment (that is, need a different paragraph) and now Dawkins' analogy works again.

What was interesting to me was that the data was highly clustered, meaning that the protein molecule of most species was very, very similar within a larger grouping, but very much different from one major grouping to another. For example mammals were similar to one another, but repties, birds, amphibians, plants, bacteria, etc. were all very different.

Not that different. The amino acid sequences show the expected nested hierarchy with closer evolutionary relatives having closer amino acid sequences. So of course mammals would be similar to each other, because they share a more recent common ancestor. But within each of the other classes of vertebrates, species within those classes are more closely related than to mammals. And all the vertebrates have more related sequences than invertebrates or plants.

Now, for someone who wants to see all the data, you don't provide any. Everyone else, if you want to do your own comparison to see if Bob is correct, many of the seqeunces are listed here: http://members.aol.com/SHinrichs9/descent/denton.jpg

Within each group there was great similarity, but each of the groups were equally distant from every other group (as measured by the number of positions which differed).

Which is exactly what is predicted by evolution, but NOT by creationism. Since all contemporary living things are cousins, not ancestor-descendents (as Denton made the mistake). So you have one ancestral cytochrome c and then variations as the descendents diverge. So, the more recent the common ancestor, the closer in the amino acid sequences are going to be.

But notice that cytochrome c refutes Bob's argument about just a few amino acid sequences to function. ALL the cytochrome c's do the same job. And ALL of them do it equally well. So instead of just one paragraph or sentence that makes sense, we have hundreds/thousands of "sentences" that make an equal amount of sense. Which means that his analogy with English sentences just went out the window.

He wrote a book, Evolution, A Theory In Crisis, and ever since he has been accused of being a creationist. Pretty funny really. He simply had honest doubts that Darwinism was the answer as to why lifeforms evolve over time.

He also co-authored Of Pandas and People. When he wrote those two books, Denton was a creationist. Not a YECer, but more an OEC/IDer. In fact, the second book is supposed to be a textbook on ID. It is the one whose original draft did use the words "creation" and "creationism" but has all those changed for "intelligent design". HIs latest book accepts evolution and drops most of the arguments he used in the first two. Which, of course, has gotten Denton is lots of hot water with his former ID buddies.

At any rate, the previous material suggests to some that the prior thinking which pretty much ignored the fact that proteins must "fold up" into a "ball" into order to function, needs to look into how often this folding will result in non-functional or subfunctional proteins.

I did this in another thread. And, as pointed out there, if the protein is critical and is truly non-functional, the individual dies. That's part of natural selection. Natural selection works on populations, not individuals. If the individual is unlucky enough to get one of the really non-functional proteins, it dies. Tough luck for it, but the rest of the population goes on just fine. The population can wait for the beneficial mutation. Sometimes, of course, those don't appear and the population goes extinct.

Fortunately this is an active field of research although it is so difficult to predict when folding occurs properly that supercomputers are being used to aid in the task.

No. There are several sites on the web that will do the Ramachandran plots for you. And the plotting of computational proteins is done on regular computers.

 

[lucaspa]

"Kimchi-Sarfaty and her colleagues studied three mutations, of which two are silent, which crop up frequently in a human protein that pumps toxins out of cells. Some versions of this protein make cancer cells resistant to chemotherapy by ridding cells of the drug; there have been hints that silent mutations might be involved."

First, notice that this is a beneficial mutation for the cancer cells! It allows them to keep from being killed by the drugs. For the human patient, that is bad. But for the cancer cell, it is GOOD! So this actually refutes Bobs' entire position! Yes, you can change the folding and get a "better" protein!

Thanks, Bob, for finding the data that destroys your own argument.

"The two silent mutations Kimchi-Sarfaty's team studied turned out to replace common triplets with much rarer ones. The body's machinery isn't as quick and adept at translating the less common bits of code. This pause in protein production could allow the protein to fold slightly differently, Kimchi-Sarfaty suggests, so that it works in a different way."

And this way is better! For the cancer cells. In this case it's not even changing the amino acid sequence, but, according to Kimchi-Sarfaty's hypothesis, just allowing a different psi angle.

"Silent mutations are known to have other effects. For example, they can change the way that RNA, the molecule that bridges DNA to protein production, is cut and spliced together. A team led by Francisco Baralle at the International Centre for Genetic Engineering and Biotechnology in Trieste, Italy, last year showed that many silent mutations in the gene responsible for the lung disease cystic fibrosis can cause splicing changes that inactivate the protein.

Or cause splicing changes that give a different protein! Bob, do you even know what "splicing changes" are? Eukaryotic genes do not have continuous DNA. Instead, a long protein will be broken up into several "exons", so you have sections A,B,C,D, and E. Most of the time thes RNA fragments are spliced so that you get ABCDE, but they can also be spliced ABCED or AEBCD or any of the other combinations. That gives different proteins -- often with different functions.

1 Kimchi-Sarfaty C., et al. Science, doi:10.1126/science.1135308 (2006).

Fortunately I have a subscription to Science. From the lay summary:

"Although these two principles can still be applied to a wealth of genes and proteins, a polypeptide chain can exist in the cell in a number of alternative conformations, revealing different functions and/or activities. For example, a neuronal isoform of cytoplasmic polyadenylation element binding protein in the sea slug (Aplysia californica) exists in two different forms: a soluble inactive form and an insoluble active form that regulates synaptic protein synthesis (4). "

"Unaffected translation kinetics results in a correctly folded protein. Abnormal translation kinetics, caused by the ribosome moving faster or slower through certain mRNA regions, can produce a different final protein conformation. Abnormal kinetics may arise from a silent single nucleotide polymorphism (SNP) in a gene that creates a codon synonymous to the wild-type codon. However, this synonymous codon substitution may lead to different kinetics of mRNA (protein) translation, thus yielding a protein with a different final structure and function."

Bob assumes that this "different final structure and function" is NO function. But that isn't what the data is saying. Instead, it is different function -- thus providing another source of variation for selection to work on.

" In 1987, Purvis and colleagues proposed that "the way in which some proteins fold is affected by the rates at which regions of their polypeptide chains are translated in vivo" (6). They hypothesized that certain "gene sequences have evolved to control the rate of translational elongation such that the synthesis of defined portions of their polypeptide chains is separated temporally." "

Hmmm. The guys who discovered this don't think it challenges evolution. Rather, they think natural selection might work to generate this difference!

"This hypothesis is very difficult to prove using in vivo systems, because numerous quality-control mechanisms exist to get rid of incorrectly or abnormally folded and misfolded proteins (8). "

Oops. Doesn't look like Bob bothered to read this part.

"The C1236T polymorphism changes a GGC codon to GGT at amino acid position 412 of the polypeptide (both encode glycine) and the C3435T polymorphism changes ATC to ATT at position 1145 (both encode isoleucine). However, both polymorphisms result in changes from frequent to infrequent codons and therefore may slow down the ribosome traffic at the corresponding mRNA regions. "

In case anyone wants the specific data.

 

[bob b]

It is really interesting to hear an evolutionist's arguments.

First, nothing you said refutes anything I said. You simply misinterpreted what I said, whether through ignorance or deliberately I cannot say. You set up so many "straw men", implying I said things I didn't, I lost count.

You did make some statements that are outrageously in error.

One that stands out is your statement that all versions of the cytochrome c moleule are essentially equivalent. Your exact words were: "ALL the cytochrome c's do the same job. And ALL of them do it equally well."

You may wish to qualify this or else make it clearer.

But this raises another of your misconceptions (not to mention the two which you cited to supposely refute my "misconceptions".

That misconception was contained in this sentence having to do with the environment. The environment is not the "paragraph" in which the "sentence is embedded". The paragraph is the servomechanism or molecular machine in which a single protein plays a "team work" role with other proteins. The environment is the ultimate external environment in which the entire lifeform operates. That is the only level at which Natural Selection operates.

A protein which was more active due to a mutation could very well upset the molecular machine of which it is only a part and cause a degradation of overall function. And of course an individual "molecular machine" is also only one component of an overall function of which multiple molecular machines are embedded (the chapter of my English language sentence analogy). The overall book or "novel" is of course the final lifeform, complete with all the "wheels within wheels" of subsystems, minor systems, and overall systems.

The reason this is so obvious to me is that my original field was in control system engineering.

Biology departments are beginning to recognize that all these levels of molecular machines can potentially be analyzed using known control system analysis techniques. This is why some universities cross train their biology students by sending them to take courses in control system theory and analysis conducted by their electrical engineering departments.

This seems to be the overall system vision you are missing.