Intelligent Design

Recent research paper in BIO-Complexity

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A friend writes to draw attention to research papers in the Biologic Institute’s journal (as opposed to review papers). This might provide a start for those interested:


 

At the very end of 2014, BIO-Complexity published a paper by Reeves, Gauger, and Axe, “Enzyme Families–Shared Evolutionary History or Shared Design? A Study of the GABA-Aminotransferase Family” which reported experimental results attempting convert various proteins to perform the function of a closely related proteins. They showed that this enzyme conversion would require more mutations than would be feasible over the history of life.

Yesterday on ENV Ann Gauger reviewed their latest research paper in BIO-Complexity, co-published with Doug Axe, “Model and Laboratory Demonstrations That Evolutionary Optimization Works Well Only if Preceded by Invention — Selection Itself Is Not Inventive.” I recommend Ann’s post explaining the paper. This is also an original research paper that reports both experimental and theoretical research.

In their 2014 paper. they had tried to convert proteins to perform the functions of other proteins. But those proteins didn’t already have the functions of the target. We often hear of a “promiscuity” hypothesis where a protein has a primary function but might also have a side activity with some weakly selectable function. In time, that side-activity might be refined and optimized to perform some new function very well. This new paper tested the promiscuity hypothesis through both experimental lab-work and theoretical simulations.

Experimental Work: The new study started with “a junk protein with weak activity against the antibiotic ampicillin, but without a properly folded enzymatic structure. It could not be improved by three rounds of random mutation and selection. In contrast, a weakly functional protein with a destabilized but properly folded structure could rapidly be optimized to wild-type levels and beyond.”

So their research suggests the promiscuity hypothesis only works if you’ve already got the right kind of functional protein fold.

Theoretical Work: They also tested this same question using Stylus, a computer model co-developed by Doug Axe that simulates Darwinian evolution in realistic manner. Here’s how Ann explains what they did:

Using a random sequence whose product has very weak similarity to the target character as a starting point, Doug asked whether it could be evolved by random mutation and selection to produce a character that resembles the archetype that was its goal. Short answer — it could not. For details see the new paper describing the work. Next he tested whether an already existing character with some weak similarity to the target could be evolved by mutation and selection to a proficient version of the target character. Once again, the answer was no. However, if the starting character was only six mutations away from optimization, it improved rapidly upon mutation and selection.

The BIO-Complexity paper presented both experimental research and theoretical research (i.e., computer simulations) that converge on a common conclusion: Selection and mutation can refine things that already have a well-honed function (i.e., as Ann puts it, “the starting protein already exists as a functional fold of the right design”). But the mechanism can’t generate new functions. In other words, it can’t generate new folds or novel functions.


See also: This is embarrassing: “Darwin’s Doubt” debunker is 14 years behind the times

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52 Replies to “Recent research paper in BIO-Complexity

  1. 1
    Ken_M says:

    Ten “research” papers in ten years.

  2. 2
    RexTugwell says:

    Ken_M, you totally shredded that Bio-Complexity paper. Well done. You zeroed right in on the substance of the research and showed where Gauger and Axe went wrong. Good on ya mate!

  3. 3
    Ken_M says:

    Just pointing out that ten papers in ten years isn’t exactly very productive for such a ground breaking, paradigm shifting theory.

  4. 4
    tjguy says:

    Yes, Ken, we would love to see more papers published, but ID does not have near the number of scientists working on it as does evolution. On top of that, there is bias against ID and sometimes articles are rejected simply because they are from the ID perspective. As Rex pointed out, let’s deal with the content. Looks like some good ole’ experimental research with results to back up the conclusions.That’s the kind of science we all respect!

  5. 5
    gpuccio says:

    Ken_M:

    Following your “logic”, I should conclude that the neo darwinian theory is certainly good, given the huge number of research papers which support it.

    And I would be wrong.

  6. 6
    EugeneS says:

    “Just pointing out that ten papers in ten years isn’t exactly very productive for such a ground breaking, paradigm shifting theory.”

    Does it have as good funding as the mainstream pharmaceutical giants driven pseudo-science?

  7. 7

    Ken M said:

    Just pointing out that ten papers in ten years isn’t exactly very productive for such a ground breaking, paradigm shifting theory.

    It’s phenomenal considering the institutional commitment against that theory and the career risk involved in pursuing or supporting such research.

  8. 8
    Virgil Cain says:

    Ken M:

    Just pointing out that ten papers in ten years isn’t exactly very productive for such a ground breaking, paradigm shifting theory.

    Evolutionism doesn’t have any peer-reviewed papers that support it. Go look and see if you can find any papers supporting accumulations of genetic accidents, errors and mistakes actually creating a multi-protein complex. No one knows how to test such a concept.

  9. 9
    SteRusJon says:

    There is an apples and oranges thing going on here, as well. Ken M, it seems to me, thinks that all those articles on the evolutionary side of the issue specifically demonstrate the viability of the evolutionary paradigm. They do not.

    I challenge Ken M to present us with a list of ten, accessible, articles over the last ten years that empirically, quantitatively, demonstrate the likelihood, or even, plausibility of the naturalistic OOL and its subsequent evolution. I would really like to read them.

    Stephen

  10. 10
    Zachriel says:

    Two scientists are talking in a lab one day and one says to the other, “Wait till you see my latest discovery. It’ll blow your mind!”

    Naturally intrigued, the second scientist asks for a demonstration of this amazing discovery. At his request, the first scientist gets a spider out of a matchbox, places it on the desk and says, “Spider FORWARDS!” At his command, the spider moves forwards.

    The scientist then says “Spider, FORWARDS”, and again the spider does exactly as it is told. The second scientist, impressed with his friend’s command of the spider, congratulates him on his work.

    The first scientist then replies, “No, you haven’t seen my discovery yet. Wait till you see *THIS*”, and he then pulls all of the spiders legs off and places it back on the desk. The first scientist then repeats his order to the spider “Spider, FORWARDS”, but the spider doesn’t move. “Spider, FORWARDS!” But it still doesn’t move.

    By this point the second scientist is getting a little confused, and so asks his friend what it is he’s trying to do, pointing out that the spider isn’t going to move. “Exactly!” the first replies. “I’ve just discovered that when you pull a spider’s legs out, they go deaf!”

    http://ednieuw.home.xs4all.nl/.....ryleg.html

    See Voordeckers et al., Reconstruction of Ancestral Metabolic Enzymes Reveals Molecular Mechanisms Underlying Evolutionary Innovation through Gene Duplication, PLoS Biology 2012: “The Present-Day Maltase Enzymes Arose from a Functionally Promiscuous Ancestor”

  11. 11
    JoeCoder says:

    There’s been more than 10 ID papers in 10 years. This volume published in 2013 had a couple dozen, and I’ve seen more in other journals.

  12. 12
    Virgil Cain says:

    Zachriel, the grand equivocator strikes again! Unfortunately Zachriel is too much of a coward to explain how gene duplications are part of blind and mindless processes.

  13. 13
    gpuccio says:

    Zachriel:

    Is that a comment to the paper? Are you not able to express your personal thoughts in an explicit and detailed way? Must you always rely on cryptic quotes, without exposing your real thoughts and taking responsibility for them?

  14. 14
    Virgil Cain says:

    gpuccio is finally figuring out Zachriel!

  15. 15
    gpuccio says:

    Well, leaving apart the question of how many ID papers exist, let’s discuss this one.

    It is very interesting indeed. I think that Axe and Gauger are trying to meet the challenge of understanding in some detail the structure function relationship in protein space, and its relations with random variation and possible NS or AS.

    I have debated some aspects of this issues many times here, and my ideas are well known.

    The findings in this paper are absolutely consistent from what we know from the scientific literature. I will simply remind that they are absolutely consistent with the findings in two of the most often quoted papers about protein evolution: the Szostak paper about evolution of an ATP binding protein by artificial selection, and the rugged landscape paper by Hayashi. The second one, in particular, absolutely supports the findings in the Axe and Gauger paper.

    The Stylus part is interesting, but certainly theoretical. The second part, about real proteins, is much more stimulating.

    A very good work, as usual, whatever Zachriel may say about spiders…

    Now, let’s listen to the neo darwinist propaganda, which certainly will do its best and worst, as usual, to deny or minimize any interesting point in this discussion.

  16. 16
    Roy says:

    On top of that, there is bias against ID and sometimes articles are rejected simply because they are from the ID perspective.

    I’ve seen that claim frequently, but never with an example. Do you have one?

  17. 17
    Zachriel says:

    gpuccio: Is that a comment to the paper?

    Yes. Voordeckers et al. find what apparently so eluded Reeves, Gauger, and Axe.

    You might also look at Scott et al. which studies a very recent evolutionary event. Scott et al., Catalytic improvement and evolution of atrazine chlorohydrolase, Applied and Environmental Microbiology, 2009: “Thus, a clear evolutionary pathway from deaminase activity to exclusive chlorohydrolase activity, via a latent promiscuous activity, can involve as few as two amino acid substitutions.”

    Experiment: Cut heart out of organism.
    Result: Organism stops evolving.

    gpuccio: the rugged landscape paper by Hayashi. The second one, in particular, absolutely supports the findings in the Axe and Gauger paper.

    Hayashi et al. didn’t include recombination, so their search was not comprehensive.

  18. 18
    Virgil Cain says:

    Zachriel is proud to be a grand equivocator. It has no shame…

  19. 19
    gpuccio says:

    Zachriel:

    From the Axe and Gauger paper:

    The common situation where an enzyme performs the same chemical transformation on multiple related substrates should not be confused with promiscuity, as the term is currently used. Mutations readily shift substrate preference in those common cases, but since the catalytic mechanism remains unchanged, shifts of that kind reveal nothing about enzyme origins.

    Recognizing this, proponents of the promiscuity hypothesis have suggested that enzyme side activities should be described as promiscuous only when two conditions are met. The first condition is that the side activity should have no physiological role, as otherwise the enzyme would be better described as multifunctional than as promiscuous [12]. The second condition has to do with the degree of separation between the side activity and the primary activity. Specifically, referring to the standard Enzyme Commission scheme for classifying enzyme functions, Khersonsky and Tawfik [12] recommend that the term “promiscuous” be reserved for cases where the EC numbers describing the primary and side activities differ in the first, second, or third index. For example, an enzyme acting primarily as a tryptophan N-monooxygenase (EC 1.14.13.125) would not be considered promiscuous if it exhibited the same activity to a lesser extent toward tyrosine (i.e., tyrosine N-monooxygenase activity; EC 1.14.13.41), but it would be considered promiscuous if it instead exhibited slight l-lysine 6-oxidase activity (EC 1.4.3.20) with no evident physiological role.

    Here are the EC classifications of the two maltases and five isomaltases in S. cerevisiae quoted in “your” article:

    MAL 12: 3.2.1.20
    MAL 32: 3.2.1.20
    IMA 1: 3.2.1.10
    IMA 2: 3.2.1.10
    IMA 3: 3.2.1.10
    IMA 4: 3.2.1.10
    IMA 5: 3.2.1.10

    As you can certainly see, the shift from maltase to isomaltase implies only a difference in the fourth EC number. I will quote again from the Axe and Gauger paper, for your benefit:

    “The common situation where an enzyme performs the same chemical transformation on multiple related substrates should not be confused with promiscuity, as the term is currently used. Mutations readily shift substrate preference in those common cases, but since the catalytic mechanism remains unchanged, shifts of that kind reveal nothing about enzyme origins.”

    Emphasis mine.

    And:

    “Khersonsky and Tawfik [12] recommend that the term “promiscuous” be reserved for cases where the EC numbers describing the primary and side activities differ in the first, second, or third index.”

    Again, emphasis mine.

    Therefore, where is it that, as you say, “Voordeckers et al. find what apparently so eluded Reeves, Gauger, and Axe”?

    Just to know.

  20. 20
    Dionisio says:

    gpuccio @19
    Noticing that you have started to dig deeper into details in the discussion -as you usually do- I feel compelled to remind you about something important.
    Please, note that last November a distinguished professor -commenting in this blog- warned that some folks here don’t ask honest questions.
    You may want to ensure that your questions meet the ‘honesty’ requirement set by that Canadian scientist.
    If you don’t understand well what he meant by ‘honest questions’ then join the club!
    🙂

  21. 21
    Zachriel says:

    From Scott et al., “Despite their high sequence similarity, AtzA and TriA are catalytically distinct; TriA is a deaminase with low dechlorinase activity, while AtzA is a dechlorinase with no detectable deaminase activity.”

    Melamine deaminase, 3.5.4.n3
    Atrazine chlorohydrolase, 3.8.1.8

  22. 22
    Dionisio says:

    Zachriel @21

    Do you know how (spatiotemporally) AtzA and TriA get produced?
    Please, you may respond just yes or no. No need to explain anything.
    Thank you.

  23. 23
    gpuccio says:

    Zachriel:

    What is wrong with you, that you can never admit that you were wrong?

    Let’s sum it up.

    In your post #10, after some obscure “joke” about spiders, you write:

    “See Voordeckers et al., Reconstruction of Ancestral Metabolic Enzymes Reveals Molecular Mechanisms Underlying Evolutionary Innovation through Gene Duplication, PLoS Biology 2012: “The Present-Day Maltase Enzymes Arose from a Functionally Promiscuous Ancestor””

    Given your proverbial reluctance to state things clearly, I asked you, in my post #13:

    “Is that a comment to the paper? Are you not able to express your personal thoughts in an explicit and detailed way? Must you always rely on cryptic quotes, without exposing your real thoughts and taking responsibility for them?”

    In your post #17, you clarify:

    “Yes. Voordeckers et al. find what apparently so eluded Reeves, Gauger, and Axe.”

    And you add:

    “You might also look at Scott et al. which studies a very recent evolutionary event.” etc.

    Now, yesterday evening, I spent some time looking at the paper you quoted twice as a rebuttal to Axe and Gauger, the Voordeckers paper, and posted in detail about it in my post #19, showing clearly that in no way it was a rebuttal of Axe and Gaugier, as you had affirmed.

    Then, having no time left in the day (it was about midnight here in Italy), I postponed to the next day the analysis of the second paper you quoted.

    I must admit that I was really curious about what you would say regarding the Voordeckers paper. To be sincere, I expected one of two things:

    a) You could simply admit that you were wrong about it.

    b) You could offer some new thoughts, either justified or more probably unjustified, to counter my arguments.

    Well, nothing of that happened. This morning I find your post #21, where you completely ignore the discussion about the Voordeckers paper, and apply the EC classification (which obviously you had not considered for the Voordeckers paper) to the other paper, as though that automatically made you right at least in that second case.

    So again I ask you:

    What is wrong with you, that you can never admit that you were wrong?

    By the way, my comments about the Scott paper will be given in my next post.

  24. 24
    Dionisio says:

    gpuccio,

    This discussion, though very interesting, is above my capacity to understand it well.

    Hence, in order for me to at least get a basic understanding of the main points being discussed here, I would like to ask a few relatively simple (and perhaps dumb) questions.

    Could the outcome of this current discussion have any effect on the clarification of the “procedures” issues that you have brought up in the past?

    Does the discussed topic help to answer the interesting “biosemiotics” questions raised by UB and others here in this blog recently?

    Could the current discussion benefit from a more accurate understanding of the spatiotemporal mechanisms (timers, epigenetics, regulatory networks, signaling pathways) underlying the production of the mentioned enzymes?

    Thank you.

  25. 25
    Dionisio says:

    gpuccio,

    when I look for updated information on the “AtzA and TriA” issue brought up by your interlocutor, I see papers on bacteria, but do not find anything describing how the mentioned bacteria came to be to begin with, or what they turn into, as result of the ‘evolutionary’ processes they refer to in some of those same papers. All I see is bacteria remaining bacteria.
    IOW, can the outcome of this “ArzA, TriA” discussion take us closer to an ‘eureka’ moment, where we can see either how we got the bacteria to begin with or how the bacteria will turn into something else next?
    The wording in those papers seem confusing and vague. It kind of reminds me of famous Mina’s “parole, parole, parole” hit song. Am I missing something here or it’s just my ignorance keeping me from seeing things clearly?
    Thank you.

  26. 26
    Zachriel says:

    gpuccio: I must admit that I was really curious about what you would say regarding the Voordeckers paper.

    As you point out, for some definitions of “promiscuous protein”, Voordeckers doesn’t apply. So we provided a different paper, Scott, which seems to do so.

  27. 27
    gpuccio says:

    Zachriel:

    Well, I suppose your #26 is as far as you can go.

    OK, I need a little time to analyze well the Scott paper, which is very technical, but I am working at it. I will give you my comments as soon as possible.

  28. 28
    gpuccio says:

    Dionisio:

    Obviously, nothing in the papers quoted by Zachriel is really relevant to the general ID issue. However, we are discussing here some of the results and conclusions of the Axe and Gauger paper, and the issues raised by Zachriel are worth of discussion.

    I agree with you that the discussion becomes very technical, but that is unavoidable. I will try to do my best to express my ideas as clearly as possible.

  29. 29
    Dr JDD says:

    10 papers in 10 years is an ad hominem argument.

    Science does not work like that. One paper demonstrating something to be mathematically impossible should be enough to falsify a proposed theory. Yes accumulation of data is important to form an opinion on a mechanism but still one single finding can destroy even a string of findings.

    So if you are going to be critical of a scientific publication, try to be scientifically critical, rather than using ad hominems.

  30. 30
    Jonas Crump says:

    JDD: “10 papers in 10 years is an ad hominem argument.”

    I believe that this was a statement of fact. As such, it is not an ad hominem. Although it is definitely an attempt at distraction.

    One paper demonstrating something to be mathematically impossible should be enough to falsify a proposed theory. “

    After it has been thoroughly critiqued and tested and found to be sound, I would agree.

  31. 31
    Dionisio says:

    gpuccio

    Yes, I agree that this type of discussion must be very technical.

    The clarity of your comments and explanations does not leave much room for improvement. You make complex technical topics easier to understand, even for those like me who know little about the discussed subjects. Sometimes I follow these technical discussions because I see that you are involved in them. Sometimes I read the OP and your comments to get an idea of the discussed subject.
    Perhaps the only ones who don’t understand your comments are those who don’t want to understand anything. In those cases there is not much you can do about it. 🙂

    I’m glad to see that the anonymous visitors to this discussion thread will be able to read your clear comment stating that the ongoing discussion about the papers referenced by Zachriel is not really relevant to the general ID issue, which you and others have described so clearly in this UD blog before. Hopefully, even Zachriel himself will eventually understand that too. 🙂

    Please, let me repeat something I have said before.

    When I worked on software development projects for engineering design systems, the functionality of most required programming tools (computers, operating systems, interactive development environments, databases, communication networks, debuggers, quality assurance procedures, etc) was ready from the beginning. Most analysts and programmers were available from the start and eager to work. Most working conditions were optimally fine-tuned!

    However, all that combined would not have helped to move the project in the right direction in order to reach the desired goal, if the director and project leader wouldn’t have explained to the rest -in an understandable manner- his main ideas about the way he envisioned (imagined) the system would work and how he wanted to build it.

    Obviously he was an excellent engineer and also consulted some potential users and many other engineers to hear their suggestions. He had brilliant ideas about resolving difficult technical issues associated with the representation of graphical information for efficient access and other fundamental conceptual problems.

    He established the procedures to develop, test, implement and deliver the product. He established the relationship with the users, gave the keynote speeches at the users conferences and made sure that customer support was at the highest level. He set the pace of development and the discipline rules. Basically, his mind was at the center of the whole project.

    Some anonymous visitors may spend quite some time reading our discussions on very technical issues that are important, but could miss the main point that at the center of it all is the directing information without which nothing else would make sense at all. This also applies to my frequent postings of references to papers in other threads, which could lead readers to get the false impression that those mechanistic research discoveries are the real deal.

    That’s why it’s good that you posted your clarifying comment @28: “Obviously, nothing in the papers quoted by Zachriel is really relevant to the general ID issue.”
    Thank you.

  32. 32
    Dr JDD says:

    Jonas Crump:

    You should look up the definition of ad hominem. It is nothing to do with facts.It is to do with essentially attacking the character of the person making the argument rather than the argument itself, which is a fallacy.

    By invoking criticism of the number of publications of the journal where this article appears, the ad hominem labels entirely appropriate to describe the nature of such a comment.

  33. 33
    Jonas Crump says:

    Dr JDD, I wasn’t defending Ken_M’s comment, just stating that it was not an ad hominem. It was definitely made in a lame attempt to discredit the journal, but a journal isn’t a person. You can’t attack the character of an inanimate object. As far as I can tell, he was accurate in his statement. But this says nothing about the quality of the articles.

    I am sorry to be pedantic, but I tend to be a little obsessive that

  34. 34
    Vy says:

    It was definitely made in a lame attempt to discredit the journal, but a journal isn’t a person. You can’t attack the character of an inanimate object.

    That is a strawman although you may be truly ignorant.

    Ever heard of the genetic fallacy? It IS a form of ad hominem. 😉

  35. 35
    Collin says:

    Roy,

    Scientific journals have often published criticisms of Behe but would refuse to publish his response. See here: http://www.trueorigin.org/behe07.php

    Although I haven’t seen “Expelled” I’m sure they talk about bias against publication there.

  36. 36
    Jonas Crump says:

    Vy: “That is a strawman although you may be truly ignorant.

    Now, that is an ad hominem. Thank you for the example Ms. Vy.

  37. 37
    gpuccio says:

    Zachriel:

    Here are my thoughts about the Scott paper. I needed some time to answer you, because I am not a biochemist, and I wanted to be sure that I understood the context as well as possible.

    I will try to be very simple. The paper is essentially about the relationship between the two proteins AtzA and TriA. The facts are:

    a) Both proteins act on two very similar substrates, atrazine and melamine. Both are 1,3,5 triazines. IOWs, they have the same ring, but different substituents. Atrazine has chloride at position 1, and two other groups at positions 3 and 5. Melamine has an amino group at all three positions.

    b) The two proteins are both hydrolases, because they both hydrolize the substituent at position 1 of the ring. That’s why they are both in the group 3 of the EC classification (hydrolases).

    However, because of the different nature of the substituent at position one, AtzA is a chlorohydrolase, and is therefore classified in the 3.8 group (halide bonds), while TriA is a deaminase, and is therefore classified in the 3.5 group (carbon-nitrogen bonds, other than peptide bond).

    IOWs, both proteins act on a similar substrate (the basic ring is the same), but they hydrolize different substituents at position 1 of the ring. That is certainly a significant difference in their biochemical activity, and that’s why they are classified in different groups at the second, third and fourth figure of the EC number.

    c) However, the two proteins are almost identical. They are both 474 AAs long, and they have 98% identity. They differ, indeed, only for 9 AAs, with no gaps.

    d) The paper essentially confirms that two of those 9 AAs are essentially responsible for the different activity. It also shows that the specific activity of AtzA can be significantly optimized by a process of artificial variation and selection, by changing a few other AAs (4, to get the most active molecule). The authors use these data to propose some model for the biochemical activity of AtzA.

    e) However, the mechanisms of action of AtzA are not yet known in detail. A crystal structure analysis of the molecule has been published for the first time very recently:

    http://www.ncbi.nlm.nih.gov/pm.....MC4356373/

    So, what does that mean?

    You offer this as an example of proteins with different activities and different EC classification which differ only for two functional AAs. That is correct.

    Is that in conflict with what Axe and Gauger say?

    They say:

    “The common situation where an enzyme performs the same chemical transformation on multiple related substrates should not be confused with promiscuity, as the term is currently used. Mutations readily shift substrate preference in those common cases, but since the catalytic mechanism remains unchanged, shifts of that kind reveal nothing about enzyme origins.”

    The situation in the case of AtzA and TriA is in a sense different but specular. Here we have two very similar proteins which act on very similar substrates, but completely different bonds. In a sense, you are right that it is a situation not described in the Axe and Gauger paper. But not a confutation of the reasonings and results in the paper.

    Indeed, two important point must be considered.

    1) The extreme sequence similarity between the two proteins is a very strong indicator that a lot of structural information is shared between the two molecules. That probably explains why a very small difference in sequence can yield different biochemical activities, at the same position of the same ring. Therefore, this specific case, even if not considered in the paper, represents a case where the “invention” is already there, at least for the greatest part.

    2) The case is certainly an extreme case. It is not certainly the general case. For example, a recent review states:

    Surprisingly, TriA, an enzyme with 98% amino acid sequence identity to AtzA, was shown to catalyze hydrolytic deamination of melamine or 2,4,6-triamino-1,3,5-triazine (46). TriA was not discernibly
    active with chlorinated s-triazine substrates.”

    Emphasis mine.

    The point is, it is certainly not the general case that two proteins so similar at sequence level may have a different biochemical activity. Indeed, this could well be the only known example.

    IOWs, we are dealing with an exception, not with the rule. The Axe and Gauger paper, instead, is trying to derive information about the general case, IOWs, about the protein functional space in general. That is a very worthwhile task, but obviously specific exceptions can exist.

    I want to be very clear here: the exception is an exception to the common relationship between sequence and function, but in no way it is an exception to the probability barriers considered in ID reasoning. That is obvious if we consider that the two proteins differ only for two functional AAs.

    IOWs, it simply shows that in very rare cases a small sequence difference in two extremely similar proteins can give significantly different biochemical activities on similar substrates. In no way it shows that in general significantly different biochemical activities can be obtained from different molecules by small sequence variations. That is, indeed, the true point analyzed in the Axe and Gauger paper.

  38. 38
    Zachriel says:

    gpuccio: 1) The extreme sequence similarity between the two proteins is a very strong indicator that a lot of structural information is shared between the two molecules.

    Of course. That’s how evolution generally works, by modifying existing structures.

    gpuccio: we are dealing with an exception, not with the rule.

    Axe and Gauger look for a black swan in their backyard. Not finding a black swan, they conclude there are no black swans.

  39. 39
    Dionisio says:

    You may have seen this before:

    For the first time since its discovery ?20 years ago, we have been able to determine the structure of AtzA, the `archetypal’ atrazine chlorohydrolase.

    AtzA appears to be structurally ill-adapted to perform its physiological function, with a metal-coordination geometry that leads to a low affinity for its metal cofactor and a substrate-binding pocket that appears to be unable to accept its physiological substrate without substantial reorganization.

    In addition, four of the active-site amino-acid residues appear to be held in strained conformations, suggesting that the active site is far from optimized, which is consistent with the relatively poor kinetic performance of AtzA (kcat/Km of ?1 × 104?M?1?s?1 and a Km in excess of the substrate’s solubility limit of 153?µM; Scott et al., 2009[Scott, C., Jackson, C. J., Coppin, C. W., Mourant, R. G., Hilton, M. E., Sutherland, T. D., Russell, R. J. & Oakeshott, J. G. (2009). Appl. Environ. Microbiol. 75, 2184-2191.]; Noor et al., 2012[Noor, S., Taylor, M. C., Russell, R. J., Jermiin, L. S., Jackson, C. J., Oakeshott, J. G. & Scott, C. (2012). PLoS One, 7, e39822.]).

    AtzA is certainly less well adapted to its physiological function than the alternative atrazine chlorohydrolase TrzN (kcat/Km of ?1 × 105?M?1?s?1 and a Km value of ?20?µM; Jackson et al., 2014[Jackson, C. J., Coppin, C. W., Carr, P. D., Aleksandrov, A., Wilding, M., Sugrue, E., Ubels, J., Paks, M., Newman, J., Peat, T. S., Russell, R. J., Field, M., Weik, M., Oakeshott, J. G. & Scott, C. (2014). Appl. Environ. Microbiol. 80, 4003-4011.]), which has good complementarity for its substrate and a catalytic mechanism that permits a broader substrate range than AtzA.

    Both atzA and trzN are prone to horizontal gene transfer, as they are located on transmissible plasmids (de Souza et al., 1998[Souza, M. L. de, Wackett, L. P. & Sadowsky, M. J. (1998). Appl. Environ. Microbiol. 64, 2323-2326.]; Sajjaphan et al., 2004[Sajjaphan, K., Shapir, N., Wackett, L. P., Palmer, M., Blackmon, B., Tomkins, J. & Sadowsky, M. J. (2004). Appl. Environ. Microbiol. 70, 4402-4407.]), and it will be interesting to see whether the catalytically superior TrzN begins to outcompete and replace AtzA in the environment.

    The structure of the hexameric atrazine chloro­hydrolase AtzA
    T. S. Peat,a J. Newman,a S. Balotra,b,c D. Lucent,d A. C. Wardenc and C. Scotta*
    BIOLOGICAL CRYSTALLOGRAPHY
    ISSN: 1399-0047
    Volume 71| Part 3| Pages 710-720
    doi:10.1107/S1399004715000619
    http://journals.iucr.org/d/iss.....index.html
    http://scripts.iucr.org/cgi-bi.....4715000619

  40. 40
    Dionisio says:

    This AtzA / TriA debate kind of reminds me of the old Galapagos finch beak shapes/size stories, where at the end finch remained finch. The same way, in this story bacteria will remain bacteria, regardless of whether they express one enzyme or another. That’s the beauty of the built-in adaptation mechanisms that allow such wide phenotype variety.

  41. 41
    gpuccio says:

    Zachriel:

    You say:

    “Axe and Gauger look for a black swan in their backyard. Not finding a black swan, they conclude there are no black swans.”

    I don’t agree. What is at stake, both in the Axe and Gauger paper and in our discussions, is the general explanation of biological evolution. IOWs, the general color of swans, not the possible existence, or non existence, of a single black swan.

  42. 42
    RexTugwell says:

    “That’s how evolution generally works”
    And from this we’re supposed to infer the rise of the spliceosome? Ain’t evolution grand?

  43. 43
    Dionisio says:

    RexTugwell @42

    “And from this we’re supposed to infer the rise of the spliceosome?”

    Of course! Why not? We just don’t understand it. 🙂
    There’s plenty of literature out there explaining it. 🙂
    But it’s not accessible to commoners like us. 🙂
    We should learn Biology 101 first, then the experts can explain it all to us. 🙂

  44. 44
    Virgil Cain says:

    Zachriel:

    Axe and Gauger look for a black swan in their backyard. Not finding a black swan, they conclude there are no black swans.

    That is your uneducated opinion, anyway.

  45. 45
    RexTugwell says:

    Dionisio, all good points. But I do love a good story. Don’t you?

  46. 46
    Dionisio says:

    RexTugwell

    Yes, I do love The Good Story.

  47. 47
    Mung says:

    c) However, the two proteins are almost identical. They are both 474 AAs long, and they have 98% identity. They differ, indeed, only for 9 AAs, with no gaps.

    An amazing example of convergent evolution!

  48. 48
    Mung says:

    Zachriel: That’s how evolution generally works, by modifying existing structures.

    Which one evolved into the other one? AtzA into TriA or TriA into TriA or both evolved from something else?

    Zachriel: Axe and Gauger look for a black swan in their backyard. Not finding a black swan, they conclude there are no black swans.

    No. Both Axe and Gauger accept that proteins exist.

  49. 49
    Mung says:

    AtzA appears to be structurally ill-adapted to perform its physiological function, with a metal-coordination geometry that leads to a low affinity for its metal cofactor and a substrate-binding pocket that appears to be unable to accept its physiological substrate without substantial reorganization.

    Of course, it’s ill-adaptedness could be just perfect for what the cell actually needs. It’s not always wise to examine things apart from their context. It might be “less than optimal” in one environment yet “optimal” in another.

  50. 50
    Dionisio says:

    Mung
    You brought up an interesting point.
    Apparently, every functionality in biology is not necessarily detectable under every condition, because sometimes it is required in very rare scenarios that are not always tested. Hence, the quoted paper seems a little inaccurate.
    Also, through history, it’s possible many things have deteriorated within the biological systems.
    Had humans stayed in Eden, none of this would have been an issue at all. But we prefer to do things our own way.

  51. 51
    Vy says:

    Now, that is an ad hominem.

    Not quite.

    You were the one claiming that Ken_M’s comment wasn’t an ad hominem because “you can’t attack the character of an inanimate object.”.

    So it’s either you were ignorant or lying. Take your pick.

    Thank you for the example Ms. Vy.

    It’s Mr. and you’re welcome 😉

  52. 52
    Zachriel says:

    gpuccio: IOWs, the general color of swans, not the possible existence, or non existence, of a single black swan.

    The paper suggests otherwise.

    Mung: Which one evolved into the other one? AtzA into TriA or TriA into TriA or both evolved from something else?

    AtzA evolved within the last fifty years to catalyze the breakdown of the herbicide atrazine.

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