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Author
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Topic: The nature of proteins: Sub-optimal design?
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Jules
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Member # 181
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posted 15. December 2002 13:43
Over at ARN, Grape Ape posted this comment a while ago:
[http://www.arn.org/ubb/ultimatebb.php?ubb=get_topic;f=13;t=000277]
"One thing I should point out, though it's probably unncessary for rafe and Mike, is that misfolded or messed up
proteins are a constant problem for the cell. There are in fact lots of mechanisms to reduce the problems caused
by
this, and I would regard proof-reading simply as one of the more elegant and sensible ones. The ER has a cool
mechanism for getting rid of (or slowing down) misfolded glycoproteins. But the most common mechanism for
dealing
with misfolded or damaged proteins is proteolysis and high turnover, which is very wasteful. The real question
from a
design standpoint is, why are proteins so prone to damage, misfolding, or bad translation? Bad design? "
I thought his comments would make a good brainstorming topic. Is there a better way to design proteins? Are there good reasons
why a designer would design proteins the way they presently exist? Does the nature of proteins make more
sense from a design perspective, or a non-design perspective?
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Cre8ionist
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Member # 140
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posted 15. December 2002 22:22
Since there are people in this forum who can do a much better job than I of detailing the
amazing capabilities of proteins, I won't even attempt it. But I'd like to touch on the sub-optimal question briefly through analogy, since it comes up quite often.
Being the Christmas season, I've had the chance to see many of the new gizmos and toys
out this year, and also, to see many of the time tested old ones. Of those older ones, Legos come to mind as quite remarkable intelligently designed building blocks.
One might think that something like these simple building blocks, while interesting, could easily be improved upon. The creations which I've seen made with these blocks, I must admit, look rather crude. Is the design therefore sub-optimal? Maybe. But the fact that they have sold so well for so long seems to argue against this. Surely though, they're not completely optimized?
Perhaps the solution lies somewhere in the middle. The Lego folks obviously think they're good enough. And that may just be the key to the dilemma. Are proteins good enough? I think so.
The real question may be, does sub-optimal design rule out intelligent design? But just take a look at some of the other creations in the shopping mall to refute that notion. ![[Big Grin]](biggrin.gif)
In any case, nobody argues against the ID of the Lego building blocks, but they do argue against the ID of the greatest known building blocks, blocks which are able to make a virtually endless variety of biological machines, go figure ![[Confused]](confused.gif) .............................Cre8
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Frances
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Member # 169
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posted 15. December 2002 23:56
quote:
The real question may be, does sub-optimal design rule out intelligent design? But just take a look at some of the other creations in the shopping mall to refute that notion.
The real problem is for ID to propose a non ad hoc theory of (sub) optimal design for it to have any scientific value imho. So far I believe that ID has not made much inroads in helping us understand the complexity in nature. One may even argue that science through its many hypotheses has fared much better. But then again science is held to a very different standard.
quote:
In any case, nobody argues against the ID of the Lego building blocks, but they do argue against the ID of the greatest known building blocks, blocks which are able to make a virtually endless variety of biological machines, go figure
Of course lego blocks do not maintain themselves at far equilibrium through metabolism. Nor do lego blocks procreate, mutate etc. Arguments from analogy run the risk of losing their value when extended beyond their intended reach.
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Jules
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posted 16. December 2002 19:24
I agree that sub-optimal design does not necessarily rule out intelligent design. But since this forum is set up to "retrain the scientific imagination to see purpose in nature," I think a good start would be trying to see purpose in the nature of proteins.
I'm not sure how we would tell the difference between an ad hoc explanation and one which wasn't. For example, it's been argued that one of the reasons for Stonehenge's design, was to act as a calendar. At what point does the explanation cease to be ad hoc?
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Joy Busey
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Member # 610
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posted 17. December 2002 10:24
quote:
Francis said: The real problem is for ID to propose a non ad hoc theory of (sub)optimal design for it to have any scientific value imho. So far I believe that ID has not made much inroads in helping us understand the complexity in nature. One may even argue that science through its many hypotheses has fared much better. But then again science is held to a very different standard.
The same prrotein can have alpha or beta fold configurations, serving different functions in the cell or system. The details of this phenomenon are not yet completely unraveled, thus it is premature to presume that because some beta configurations are deadly, the “design” of proteins in general is sub-optimal.
Evolution depends upon genomic changes, which arise by any process that is neither fatal to the organism nor caught by the redundant (and highly sophisticated) genomic and cellular repair mechanisms, and is incorporated in reproductive cells as heritable variations. There are real constraints on the process of evolution as well as the processes of life. Life forms have become increasingly complex (evolution tells us), to the point that there are intelligent living beings asking questions about how the processes work. Most biochemical processes work via proteins.
So I’d say it’s a pretty good design, even if a quirky and error-prone on individual levels. Life forms must be mortal in order to sustain (and environmentally justify) reproduction, and reproduction is the vehicle of evolution. Evolution thus requires a certain instability, a limitation on the length of time an individual organism gets to contribute to the process. Death is the end result of life because that’s how life in time (as we know it) works. It’s great if we can pinpoint the cause of diseases that plague us and mitigate them by design. But death will still be universal in every generation, or there is no room in nature for generations.
I do not see how we - as seekers of knowledge about nature - can legitimately label any process or product of nature to be “sub-optimally designed” just because the results don’t meet our subjective desires or standards. Nature is what it is. If it were something else, it would be something else. We are also products of life and evolution - natural engineers because we can reconfigure nature to our designs, using the processes of nature that we can understand and manipulate [FAPP].
Against what do we weigh nature to determine that nature’s designs are “sub-optimal?” There must surely be an objective measure for such a judgment. It can’t be measured against our intelligent ability to discover the designs, if our intelligence and abilities are part of the design. It can’t be measured against our personal angst about mortality, if mortality is part of the design. And it can’t be measured against our conceptualizations of any supernatural deity or ideal, since those conceptualizations are products of our natural minds - part of natural design, but not part of objective reality.
So it would seem pertinent for those arguing the sub-optimal status of nature’s designs to qualify their yardstick. In what way are proteins sub-optimally designed to do the jobs they do?
- Joy
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Jules
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posted 17. December 2002 14:04
Joy, it didn't sound like Grape Ape was saying that because some beta configurations were deadly, therefore proteins are sub-optimal. It sounded like he was saying that there are continuous problems with proteins in the cell, and that a great deal of the cell's energy is spent trying to correct them. And wouldn't an intelligent designer have come up with a more efficient design?
You've suggested that part of the answer is a sort of built-in obsolesence. And since I don't know anything about the connection between problems with proteins and the death of a cell, perhaps you're right. Is there a connection?
[ 17. December 2002, 17:36: Message edited by: Jules ]
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Josh
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Member # 405
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posted 17. December 2002 14:22
This is certainly my favorite topic in the area of evolution and I believe it bears direct importance on the legitimacy of the entire ID movement. The essential element of the topic is the nature of protein sequence, folding and function. I don't want to offend anyone here, but the following is basic protein biochemistry and has direct relevance to the topic: proteins have a primary, secondary, tertiary and quaternary structure. The DNA sequence of any gene is converted into a specific amino acid sequence (imagine a chain and adding one link at a time at one end until you form a full-length chain), and this is called the primary structure of a protein. The secondary structure is the elemental "mini" folds such as alpha helices or beta strands that can form in 20 amino acid stretches by themselves. These secondary structural motifs are then organized and folded into an overall global three-dimensional protein fold called the tertiary structure (which requires the entire sequence with the exception of domains...) Finally, several tertiary-structure folded proteins combined together (such as the four subunits of hemoglobin) give you a superstructure dubbed the quaternary structure. Generally protein function arises out of the properties of the tertiary and quaternary structure folded protein, not earlier folding intermediates (in fact unfolding kills function as the topic alludes to.) So the essence of protein folding and subsequently protein function in general is how to generate an active protein from an unfolded polypeptide chain. As you can imagine you can fold a normal chain in an infinitely great number of ways, you can pull it out straight or dump it in a pile and the links can fall into the pile in any number of ways. For a protein chain, what dictates its folding is how it interacts with other parts of the chain, and its environment- mostly aqueous for biological systems. The following is a relevant section from "Biochemistry" by Lubert Stryer (p. 418):
quote:
"How are the harmonic chords of interaction, to use Anfinsen's metaphor (p.39)...
Anfinsen's Metaphor from Page 39 for your reference:
It struck me recently that one should really consider the sequence of a protein molecule, about to fold into a precise geometric form, as a line of melody written in canon form and so designed by Nature to fold back upon itself, creating harmonic chords of interaction consistent with biological function. One might carry the analogy further by suggesting that the kinds of chords formed in a protein with scrambled disulfide bridges, such as I mentioned earlier, are dissonant, but that, by giving an opportunity for rearrangement by the addition of mercaptoethanol, they modulate to give the pleasing harmonics of the native molecule. Whether or not some conclusion can be drawn about the greater thermodynamic stability of Mozart's over Schoenberg's music is something I will leave to philosophers of the audience.
...created in the conversion of an unfolded polypeptide chain into a folded protein? One possibility a priori would be that all possible conformations are searched to find the energetically most favorable one. How long would such a process take? Consider a small protein with 100 residues [amino acid chain lengths]. Cyrus Levinthal calculated that if each residue can assume three different positions [a very conservative range of positions], the total number of structures is 3^100 power, which is equal to 5 X 10^47. If it takes 10^-13seconds to convert one structure into another, the total search time would be ... 1.6X10^27 years! Clearly it would take much too long for even a small protein to fold properly by randomly trying out all possible conformations. The enourmous difference between calculated and actual folding times is called Levinthal's Paradox.
The way out of this dilemma is to recognize the power of cumulative selection. Richard Dawkins, in The Blind Watchmaker, asked how long it would take a monkey poking randomly at a typewriter to reproduce Hamlet's remark to Polonius, "Methinks it is like a Weasel." An astronomically large number of keystrokes, of the order of 10^40, would be required. However, suppose we preserved each correct character and allowed the monkey to retype only the wrong ones. In this case, only a few thousand keystrokes on average would be needed. The crucial difference between these cases is that the first employs a completely random search [the hemoglobin number] whereas in the second, partially correct intermediates are retained.
The essence of protein folding is the retention of partially correct intermediates. However, the protein folding problem is much more difficult that the one presented to our simian Shakespeare. First, proteins are only marginally stable. The free-energy difference between the folded and unfolded states of a typical 100-residue protein is 10kcal/mol. The average stabilization per residue is only 0.1kcal/mol, which is less than random thermal energy (RT=0.6kcal/mol at room temperature). This means that correct intermediates, especially those formed early in folding, can be lost. The analogy is that the monkey would be quite free to undo its correct keystrokes. Second, the criterion of correctness is not a residue-by-residue scrutiny of conformation by an omniscient observer [as Dawkins analogy provides with the computer program] but rather the total free energy of the transient species. Intermediates can be scored only by their free energies. Third, some intermediates, called kinetic traps, have a favorable free energy but are not on the path to final folded protein form. No wonder then that protein folding is such an intriguing problem for both theoriticians and experimentalists."
Basically this excerpt of text emphasizes the fact that protein folding is thermodynamically identical to taking a regular chain, throwing it in the air, and allowing it to fall on the ground however it likes. Somehow, and the greatest mystery for protein folding experts, every time a protein chain is tossed into the air, it falls on the ground in a very precise and exact fashion despite the minimal energetic benefit of such a conformation. In layman's terms, a protein is just as stable completely unfolded (WITH NO FUNCTION) as it is folded (WITH FUNCTION.) So for protein folding biologists the difference between a functional and non-functional protein is very very little- so minimal as to baffle experts why it ever folds correctly in the first place with such rapid kinetics.
So to return to the point about sub-optimal function, I think it is extremely wrong to characterize the UPR or other folding proof reading mechanisms as a proof of sub-optimal protein function. Experts are well aware at the mystery of how any protein folds correctly and maintain sheer amazement that the proteome is actually capable of folding. The UPR only stands as a proof-reading capacity of what proteins normally do all on their own (and sometimes with the help of chaperones.) The fact is, proteins are AMAZING in their design and folding properties and function. There is no such thing as sloppy design that has been detected in protein biochemsitry, in fact quite the opposite is evident. It is amazing that every single protein doesn't require an active UPR, chaperone, and everything else just to fold correctly.
Additionally, unfolding of proteins is a very poor indication of optimal or sub-optimal design. Two proteins I work on change their fold in response to different signalling cues. In other words, the ability of a protein to change conformations actually has a very important role in its ability to perform its job. So imagine the protein fold not like the shape that a lamp has (very definite and structured), but more the shape that an amoeba has changing in many different, but limited ways for a very specific purpose. For anyone to claim that the conformations of a protein are sub-optimal is for them to claim that they know every singe function of a protein and have identified that a particular conformation is detrimental to the organism.
The UPR is a response to "detrimental" protein conformations, but occurs only when proteins are being expressed under very abnormal and stressful conditions like maxed out protein expression. If you take into consideration how phenomenally difficult it is to predict or determine how or why any protein folds into a stable and specific conformation AT ALL, it is no surprise that one might help out protein folding under extreme conditions by a sensitive pathway that can detect the accumulation of unfolded proteins. Additionally, proteins are sorted during processing so that unfolded proteins won't be shipped for final delivery before they are properly folded. Again, this isn't sub-optimal protein design, but thorough proofreading of proteins that are not only being folded, but enzymatically processed and sorted for shipping to various parts of the cell. It is also a process that facilitates the folding of a protein such that it won't achieve some random final fold like a kinetic trap, but the functional and specific tertiary and quaternary structures that the proteins have been designed to assume. To label any of this as sub-optimal protein design is a complete MISNOMER and ignores everything we know about protein folding. One might possibly question if amino acid sequences are the optimal basis for biologically active molecules, but one might as well start speculating on the number of alternative universes that exist and are undetectable IMO.
It is also a basic understanding of proteins to talk about their turnover. Proteins are synthesized and degraded at different rates depending upon the need of the system. Additionally, proteins have various life expectancies, they can unfold or become inactive in many different ways (chemical agents, thermal peterbation, etc.) and inactive proteins are destroyed. But to say that the existence of protein destruction shows sub-optimal design is another misnomer. The lifetime of certain proteins is essential to their regulation and function; the cell cycle would not occur properly if protein degradation did not happen every time a cell divides. Likewise other proteins may need to be degraded so they only do their job in a specific window of time-- it can be very detrimental to allow proteins to always do what they do, you need to turn them off. So again, the presence of misfolded, or degraded proteins actually says very little about their sub-optimal nature.
So, how does all this relate to the ID movement? Well, let's consider what the theory of evolution requires. It requires that basic biomolecules such as amino acids, self assimilated into the diversity of life present in modern day organisms. That means, for every single genetic sequence (and protein known) the following sequence of events must have occured (ignoring the RNA world for now):
Completely Random Protein Sequence
--Transition I-->
Stably folded, biologically active protein sequence
--Transition II-->
Optimized Diversity of Function derived from similarly folded protein sequences
One of ID's prominent concepts is that you cannot build an irreducibly complex machine from random parts through gradual mutations. Regardless of the merits of the Organisms built by GAs thread (which I don't have the time to wade through) all this discussion begins with proteins that have already been endowed with stable folds and biological functions. The real issue is how in the world can evolution derive function from completely random sequences that have no function?? By default natural selection cannot select something which does not perform any function. A fundamental question is how much function can any given protein sequence have? Think of the following relationships:
All Possible Protein Sequences
Causally relates to
All Possible Protein Folds
Causally Relates to
All Possible Protein Functions.
Cumulative selection, as mentioned earlier, is no solution unless you give an omniscient observer the capability of maintaining partial intermediates that don't have selectable function. The whole argument here centers on a personal judgement: how many of the total possible protein sequences perform positive- naturally- selectable- protein functions (and also how many intermediates are there from completely random sequence to stable biologically active sequence that have any function at all. If only a stable final protein fold as occurs today has any function toward given activity X, evolution cannot happen by small steps, the whole protein has to appear at once to get any function and you are left with insurmountable odds dubbed the "hemoglobin number.") The fact that we haven't uncovered the function of a large percentage of all proteins available in all genomes indicates that not only do we not know what all proteins currently do, we have no idea of what all possible proteins could possibly do. It is a matter of sheer speculation to conclude that evolution is possible (and likewise, to boldly assert that it is not possible unless the explanatory filter can work effectively) and even more so to make any comments currently on the optimization of protein design, imho.
[ 17. December 2002, 14:57: Message edited by: Josh ]
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Joy Busey
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posted 18. December 2002 09:41
quote:
Jules said: Joy, it didn't sound like Grape Ape was saying that because some beta configurations were deadly, therefore proteins are sub-optimal. It sounded like he was saying that there are continuous problems with proteins in the cell, and that a great deal of the cell's energy is spent trying to correct them. And wouldn't an intelligent designer have come up with a more efficient design?
There are some proteins with beta forms that are deadly, but more often both the alpha and beta configurations have uses in biological processes. And I seem to recall from long-ago training that the breaking down of proteins is also part of the general processes of cells. Which can either eliminate proteins from the vicinity or body or re-use amino acids thus liberated to assemble new proteins. All cellular processes are energetic.
Do you have a figure here for how much cellular energy is “wasted” cleaning up after its many processes? You (or “Grape Ape,” whoever that is) have suggested that proteins are sub-optimally designed to do the rather amazing jobs they do in organic processes. Apparently because they sometimes mis-fold. But you have not indicated how one determines that either an alpha or a beta configuration is an incorrect configuration for a given process, how often a “wrong” configuration occurs in the course of metabolic production of proteins. Nor have you indicated whether the errors you cite are the product of point mutations causing amino acid substitutions, RNA errors, signalling errors or folding errors.
I think that the question “Are proteins sub-optimally designed?” needs some qualification so we know precisely what about proteins (or cellular/extra-cellular processes using proteins) might be considered sub-optimal. And it might also be useful to postulate what might be considered optimal for the tasks proteins do in the processes of life.
quote:
You've suggested that part of the answer is a sort of built-in obsolesence. And since I don't know anything about the connection between problems with proteins and the death of a cell, perhaps you're right. Is there a connection?
Cell death is a different (but also naturally programmed) process. And as I said, neither the dynamic data-processors we call “life” nor the phenomenon of life called “evolution” could occur in the absence of programmed obsolescence... death, universal in all generations. It’s quite the efficient system. So in answer, I’ll cite what Josh said about it -
quote:
Josh said: To label any of this as sub-optimal protein design is a complete MISNOMER and ignores everything we know about protein folding. One might possibly question if amino acid sequences are the optimal basis for biologically active molecules, but one might as well start speculating on the number of alternative universes that exist and are undetectable IMO.
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Jules
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posted 18. December 2002 21:58
Joy,
Very good questions. Too bad I don't know any of the answers. I quoted Grape Ape's comments, because I thought they would be a good start for a thread. Does anybody know how often proteins are prone to misfolding, damage or bad translation?
Josh,
Thanks for all the information. In case you can't guess, I know next to nothing about proteins. I'm just trying to be a catalyst for getting people to think about things teleologically. But unless critics who know a whole lot about proteins respond pretty soon, there won't be much thinking going on in this thread. It sounds like you've made a fairly good case for seeing purpose in the nature of proteins. So let me ask you: Do you see things about proteins that make you think, "Why would someone design it that way?"
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Stephen Wright
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posted 19. December 2002 12:55
Jules quoted Grape Ape,
quote:
“But the most common mechanism for dealing with misfolded or damaged proteins is proteolysis and high turnover, which is very wasteful. The real question from a design standpoint is, why are proteins so prone to damage, misfolding, or bad translation? Bad design? "
I think is there is a dual interpretation to the above. The design can be for a particular mechanism or it can be a process design. A low capability to produce quality for a piece of equipment (quantified as Cpk, Ppk or Cmp) is seen to point to a poor design. However, the statistical values for capability derived from a process consisting of a number of systemic mechanisms is determined by all the out of spec product statistics from each and every mechanism and by raw material variances. I suggest that the issue here, with protein folding, is a process issue and that the process flow is “designed” with the informational content and flow in mind.
Information transmission must account for noise. Noise, or poor quality channels of transmission will cause interference and hence garbled messages. Some noise is inevitable. The process of protein creation needs to have error correction. Additionally, the removal of poor quality by-products needs a way to recognize incorrect transcription and translation and a means of purging what is recognized. A good process design accounts for elimination of by-products from the process. Proteolysis seems to be a component of an organized and fully systemic process structure correlated to getting the most from a difficult task.
I don’t see bad design here, only a process design with a capability related to the problems of control and command of the information and noise in the cell environment.
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Josh
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posted 19. December 2002 15:13
quote:
Thanks for all the information. In case you can't guess, I know next to nothing about proteins. I'm just trying to be a catalyst for getting people to think about things teleologically. But unless critics who know a whole lot about proteins respond pretty soon, there won't be much thinking going on in this thread. It sounds like you've made a fairly good case for seeing purpose in the nature of proteins. So let me ask you: Do you see things about proteins that make you think, "Why would someone design it that way?
Well, I know something about proteins, and words like teleology and epistemology scare me. I look them up every time I respond to someone who uses them because I never know exactly what they mean... I'm no philosophy major.
As for the purpose of proteins, this is very evident regardless if maximal naturalism or christian or any other theism is right. Either nature procured these amazing things or God, or some combination therein, but their design and purpose (function is a bettter term for purpose here) is pretty clear.
What about proteins make me think why anyone would design them that way? Well, as I alluded to, in a general sense, our knowledge of protein biochemistry is quite limited compared to what can be known. However, from this limited subset of information one prominent question that gives me seizures thinking about (since I am prone to agree with the Intelligent Design Movement on many things) is why God would create such nasty proteins used by pathogens (disease causing microorganisms.) There are clearly some very well designed proteins that kill, destroy, maim and do terrible things to host organisms in a very wide spectrum of specific and purposeful ways (i.e. many different types of proteins from pathogens are used to attack many different types of host organism processes.) In fact, some organisms appear to have their entire genomes/proteomes devoted to destroying host organisms, like the AIDS virus for example. Why would God, creator of all things supposedly, create such a diverse set of detrimental proteins? If he didn't who did, and what supports the idea?
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Grape Ape
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posted 20. December 2002 01:58
Hello all. It's been awhile since I checked in on this forum, and I must say I was a bit surprised to see Jules quoting me from an old thread on ARN. I'm flattered. ![[Smile]](smile.gif)
One thing I want to point out is that the quoted text attributed to me needs to be looked at in the context of the entire thread, for which poster rafe gutman provided much more substantive discussion. This was basically his critique of one of Mike Gene's essays, and by extension, the approach Mike takes to ID. Now as I understand it, Mike takes a much different approach than does someone like Bill Dembski, who insists on detecting design by finding CSI (i.e., impossibility of natural mechanisms). Mike instead (and I apologize Mike if I'm misunderstanding you) tries to use an ID perspective to drive hypotheses about cellular life by assuming that it was designed, and then asking himself how a clever designer would have done things.
Anyway, I don't want to regurgitate the whole thread, but the context was proofreading at the level of both transcription and translation. From Mike's way of thinking, these are mechanisms for optimizing the likelihood of getting the information from a DNA sequence into its protein product while minimizing the number of mistakes, and therefore minimizing the likelihood of misfolding and/or loss of activity, with subsequent degradation and waste. Of course this is my way of thinking too, we just differ on how we thought it likely came about. My question was meant to get at the heart of the issue: If the cell and its components were so superbly designed, then why would proofreading be necessary in the first place? Why design something that was so prone to error that it needs two levels of proofreading and still needs high levels of turnover?
There's a couple of ways of looking at this. For one thing, I agree with a lot of posters here who have pointed out that we can't say that the proteome and its tendency to need high turnover really is suboptimal. This is because we don't really have an "optimal" system to compare it to. Josh did a good job of pointing out some of the intricacies of protein folding and dynamics, and I'll address some of his other points below. And given his arguments, one really can say, "Wow, look at how well designed this is". But this just begs the question of why it's so tough to get them to fold right in the first place. If we found a system where the catalytic and structural units always folded fine (or never needed to fold) then we would have every reason to see design there too, because this would be elegant simplicity. So the problem being, if we really can't say whether or not the current system is suboptimal, then we can't really say that it looks well designed either. Afterall, suboptimality is more or less defined as the opposite of good design. And I think Jules was being very perceptive in seeing this as something that makes it difficult to see "purpose" in nature. Thus the reason why it's relevant to Mike Gene's (and others) view of using ID. My take on the whole thing is that it doesn't help to pretend like the cell and its components were designed, because if they were, then they are of a type of design that we have no familiarity with. The fact that we can't conclude what is and isn't suboptimal proves this point IMO.
Now for some more general stuff about protein folding and evolution. Josh gives us a very educational post about some of the complexities of protein folding and what it means to biology. I'm going to skip most of the stuff about the dynamics of protein folding, because I think, at least as it relates to the suboptimality argument, I've addressed that above, and also because I don't have the necessary background in physics to know that much about it. I think Josh can appreciate that, because he notes that there's tons of stuff that we don't know. The literature on the dynamics of protein folding is very large, but it's also difficult to read (for me anyway). But I have reviewed some of the literature at it pertains to the evolution of protein folds, and I'll present some of that.
First of all, it’s a misconception even among many biochemists that all proteins need to fold to be functional. In fact, the importance of disordered proteins and those with long disordered regions is now becoming more clear. Try searching the lit for “intrinsically disordered proteins” and you’ll come up with a number of hits. These proteins (or certain domains) are unfolded and yet are perfectly functional, and in many cases are just as highly conserved as folded protein domains, though often of lower sequence complexity [1] (and hence, easier to evolve via random generation). In fact, there is evidence that disordered proteins outnumber ordered proteins, but that the ordered ones represent more resolved structures in the PDB simply because (big shock) they’re easier to crystallize. So one possible way for folded proteins to come about is by evolving from functional yet disordered proteins, and in this case there would never be a period of time when there was not a selectable function. And of course it’s not like there are only two kinds of proteins, folded and unfolded. There is also the intermediate molten globule state.
However, most protein folds are thought to evolve from other folds. This can be seen with the arrangement of protein folds into scale free networks. Two recent papers on this are relevant. The first one is Proc Natl Acad Sci U S A 2002 Oct 29;99(22):14132-6, Expanding protein universe and its origin from the biological Big Bang. I posted a number of excerpts from this paper here, so I won’t bother reproducing them. The point however is that the scale-free network in which protein folds fit is highly indicative of a duplication / divergence process from one or a few initial folds. The second paper, which came out about the same time, is Nature 2002 Nov 14;420(6912):218-23, The structure of the protein universe and genome evolution. Here’s the abstract:
quote:
Despite the practically unlimited number of possible protein sequences, the number of basic shapes in which proteins fold seems not only to be finite, but also to be relatively small, with probably no more than 10,000 folds in existence. Moreover, the distribution of proteins among these folds is highly non-homogeneous -- some folds and superfamilies are extremely abundant, but most are rare. Protein folds and families encoded in diverse genomes show similar size distributions with notable mathematical properties, which also extend to the number of connections between domains in multidomain proteins. All these distributions follow asymptotic power laws, such as have been identified in a wide variety of biological and physical systems, and which are typically associated with scale-free networks. These findings suggest that genome evolution is driven by extremely general mechanisms based on the preferential attachment principle.
So both of these papers support the idea that an evolutionary process not only can account for the emergence of protein folds, but that the distribution of folds is a predicted consequence of evolution.
Now finally, if you want a “beginning to end” account for protein evolution, there is this recent review article (and there are others out there):
FEBS Lett 2002 Sep 11;527(1-3):1-4, Molecular evolution from abiotic scratch.
I’ll see if I can reproduce what they’ve got listed as the five stages of protein evolution, though I’ll have to skip the discussion:
1. Homopeptides of Ala and Gly encoded by (GCC)-(GGC) duplexes.
2. Mixed peptides of two alphabet types.
3. Chains of optimal length close the ends by interactions between two amino acid residues.
4. The loops are joined in linear arrays and form folds (domains)
5. Modern, multidomain proteins are formed.
I don’t know if this model will last, or even if it can stand up to serious scrutiny right now, but it’s the kind of thing that needs to be explored in detail before we can really say anything about the likelihood of protein evolution de novo. Keep in mind that this particular model is trying to account for the evolution of proteins from the origin of life, which is necessarily tricky because it’s difficult to learn about this just from looking at modern life. However, once you have a functioning cell, I don’t see any problem with the ability of current theory to account for protein evolution.
[This last reference is at the end here for no real good reason]
1. Proteins 2001 Jan 1;42(1):38-48, Sequence complexity of disordered protein.
quote:
Intrinsic disorder refers to segments or to whole proteins that fail to self-fold into fixed 3D structure, with such disorder sometimes existing in the native state. Here we report data on the relationships among intrinsic disorder, sequence complexity as measured by Shannon's entropy, and amino acid composition. Intrinsic disorder identified in protein crystal structures, and by nuclear magnetic resonance, circular dichroism, and prediction from amino acid sequence, all exhibit similar complexity distributions that are shifted to lower values compared to, but significantly overlapping with, the distribution for ordered proteins.
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Mike Gene
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posted 20. December 2002 02:46
I had forgotten about that thread. A few late night thoughts on the real issues:
My question was meant to get at the heart of the issue: If the cell and its components were so superbly designed, then why would proofreading be necessary in the first place?
I can think of two possible explanations, which are the same as the ones I applied to cytosine deamination.
The first explanation may entail necessity - the inability to create an error-proof polymerase (without significant deleterious effects some other feature, like rate of polymerization). Consider DNA- the basis for discrimination is very subtle as the four nucleotides are quite similar. Normally, A binds to T and G binds to C, but mismatching is clearly possible as H-bonds can form between C/A and T/G (through wobble-like interactions). I have not read the free energy calculations, but I suspect the differences between Watson-Crick base-pairing and some of these other forms of base-pairing are quite small. In fact, what is interesting about DNA pol I from E. coli is that it discriminates through subtle conformational shifts that depend on the base pair conforming to the geometry of standard Watson-Crick base-pairs (where non-WC base-pairs have only a modestly different geometry with respect to distances between the C-1' carbons of the sugars and with respect to bond angles).
To use an analogy, the DNA polymerase is not reading a string of red, green, white, and black beads. It is reading four beads that are closely continuous shades of gray. We're talking about discrimination near the threshold where the basis for discrimination begins to fade away. And we're talking about doing it very quickly and very well .
Now, why do cells require proofreading? Apparently, even though DNA pol is about as good as you can get, this is not sufficient for faithfully replicating the amount of information needed to sustain and propagate life. Life is more than complexity; it is specified complexity. Of course, one might want to argue that a designer should have designed another form of genetic material, or perhaps another Universe with a different set of Laws, simply in order to do without the handful of gene products needed to proofread. But this "should have" argument is purely a speculative metaphysical argument where we have not a single shred of evidence that these other imaginary and undefined states would be any better. For example, say we design genetic material whose characters are easier to distinguish. Easy to imagine, eh? But what does this mean in terms of the metabolic machinery needed to make the characters? Would we trade the few proofreading gene products for even more character-synthesizing enzymes that might require even more energy? Would a template strand with very different characters be more "bumpy" so that it slows the polymerase or makes it harder to package the genetic material?
Proofreading may simply mean that life is built around specificity at a micro-level so small that the ability to specify is nearly unobtainable. That is, just about at the threshold where specificity becomes possible, there we find the process we call life. This doesn't speak of kludginess to me (a membrane bag full of random second order reactions speaks more of kludginess). It speaks of design at a very impressive level.
Of course, then there is the second possibility (which need not exclude the first one):
Why design something that was so prone to error that it needs two levels of proofreading and still needs high levels of turnover?
Why think there is anything wrong with proofreading or high turnovers? While such features may appear inefficient, they serve another design objective very well - flexibility. If you have two levels of proofreading and turnover, you have three nodes of regulation. Nodes that can also be exploited by a designer trying to front load evolution.
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Joy Busey
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Member # 610
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posted 20. December 2002 11:45
Hello, Mike. A few observations and thoughts if you please...
quote:
Mike Gene said: Proofreading may simply mean that life is built around specificity at a micro-level so small that the ability to specify is nearly unobtainable. That is, just about at the threshold where specificity becomes possible, there we find the process we call life. This doesn't speak of kludginess to me (a membrane bag full of random second order reactions speaks more of kludginess). It speaks of design at a very impressive level.
I suspect the “kludginess” you speak of (the bag full of second order reactions) is entirely a misconception engendered by the SOP of biology - “cut ‘em up, ‘fuge ‘em out.” A bit like blowing a house into toothpicks in order to study its decor. If you haven’t read Mae-Wan Ho’s “The Rainbow and the Worm” [subtitled: The Physics of Organisms], you should. Her approach was to study organisms in vivo, and using some new nifty devices of optical physics, to study their biophoton emission dance (looks to be organized and specified).
In addition, Johnjoe McFadden’s book “Quantum Evolution” gets down to the nitty-gritty of what it actually means for an atomic particle (as postulated “piece” of a given biological molecule) to maintain a coherent superpositional wavestate in the m/secs just prior to its being “observed” by the system in order to accomplish some action or reaction. According to McFadden, this would be the particle’s sampling of all probabilities for its final form/function. A phase change signalling the beginning of a process, then another phase change to facilitate the process. This would apply to enzyme actions, protein configuration, etc.
Thus the “proofreading” functions of separate molecules active in the process initiated must exist in order to accomplish the process - because one or more particles may be operating in a different form from what they were prior to initiation of the process. This is of course dynamic on a number of levels, but that’s certainly an observable aspect of organisms and their information processing abilities.
The final form of any “piece” of an atom of a given molecule is constrained by the pdf for that wavefunction once it goes into the quantum sampling state. Though final form must of course determine the function (to the organic system) of the process it is part of. Here is where the NDS would like to build its wall of acausality, and here is where intelligent design would be most detectable. Rather than being acausally random, the sampling process could allow specificity - choice of state for control of a macrobiotic process.
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Why think there is anything wrong with proofreading or high turnovers? While such features may appear inefficient, they serve another design objective very well - flexibility. If you have two levels of proofreading and turnover, you have three nodes of regulation. Nodes that can also be exploited by a designer trying to front load evolution.
In any energy-intensive dynamic process there is (by universal law) a “high turnover rate” of what engineers like to call “wasted energy.” No perpetual motion machines, IOW. It would seem to me that in order to postulate a more efficient (or better designed) energy-intensive dynamic system, one would have to suspend the laws of physics as we observe and define them. So my question would be why is it the Darwinian Orthodoxy [disguised as science] asserting sub-optimal design, if the only alternatives that can be conceived either violate natural law or cease being dynamic entirely?
Design, on the other hand, can easily account for the dynamism and energy loss involved in complex biological processes by tracing them down to the most basic information processing levels. Information is raw data, but processing information requires intelligence - programming. If that programming is at root non-deterministic, it must be intelligent just to explain the existence and relative stability of organic life forms.
[ 20. December 2002, 11:50: Message edited by: Joy Busey ]
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Josh
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Member # 405
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posted 31. December 2002 20:00
Sorry for the delayed response, I have been away on holiday (and grounded myself from spending too long on any computer…)
quote:
But this just begs the question of why it's so tough to get them to fold right in the first place. If we found a system where the catalytic and structural units always folded fine (or never needed to fold) then we would have every reason to see design there too, because this would be elegant simplicity.
--I see this as equivalent to speculating on the number of alternative universes that exist but are undetectable. It would be a lot more productive to simply focus on how biology looks to us now.
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So the problem being, if we really can't say whether or not the current system is suboptimal, then we can't really say that it looks well designed either.
--Levinthal's paradox clearly indicates that as far as we can tell, the current system is exquisitely optimal, beyond any and all imagination, since we cannot at all understand HOW PROTEINS FUNCTION AT ALL, not to mention "how they function optimally." The fact that proteins function (within the scope of our current knowledge) indicates strongly that the system is well optimized. Until contrary evidence appears, basically resolving levinthal's paradox, I think we can assume that the proteome is optimal. (And I think any assessment of the situation taking levinthal's paradox into consideration would strongly argue pro-optimum.) Both evolutionists and design theorists should say the same: several billion years of refinement by selection/ intelligent construction should lead to very little suboptimal design in current systems. I find it a little inverted when someone argues opposite as evidence for evolution because they found some sloppiness. Shouldn't a billion years be enough time for exquisite refinement? I think so, and I think that the data support that regardless of the ultimate truth of Darwinian evolution/Intelligent Design.
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Afterall, suboptimality is more or less defined as the opposite of good design. And I think Jules was being very perceptive in seeing this as something that makes it difficult to see "purpose" in nature.
Especially when ignoring levinthal's paradox (not to be too redundant.)
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My take on the whole thing is that it doesn't help to pretend like the cell and its components were designed, because if they were, then they are of a type of design that we have no familiarity with. The fact that we can't conclude what is and isn't suboptimal proves this point IMO.
If we imagine evolution is solely responsible for the origin of the proteome, we are no more familiar with the type of "complexity" exhibited by the proteome than if we "imagine a designer." Imagining evolution or design still leaves the mystery of protein folding and function unresolved. This argument is incredulity at its best. Again, compare what we know about how/why proteins fold so well with how well they actually fold, and optimization rules the day. Now if you compare with some abstract and unknowable perfect reality (which we can't currently say isn't true to some extent of the proteome) then perhaps you might say that we can't know the exact degree of sub-optimal protein construction. But none of this gives great support for either evolution or design.
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First of all, it’s a misconception even among many biochemists that all proteins need to fold to be functional.
But it is not a misconception to say this statement "generally," as I did, although how general this statement is has not been strictly proven.
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These proteins (or certain domains) are unfolded and yet are perfectly functional, and in many cases are just as highly conserved as folded protein domains, though often of lower sequence complexity [1]
I recently attended a lecture by a protein folding expert who related some of the importance of these examples to us. The take home was that this scenario allows for the ability of a protein to acquire extremely high specificity without unwanted excess of affinity. In this scenario, the unstructured domain becomes structured upon binding and then reversed when unbound and the energetic difference between the folded states offsets the affinity necessary to acquire high specificity. This seems to be an ingenious example of design, incorporating very clever construction for a very specific purpose. There are other types of unfolded domains though, for example domains that allow flexibility so a protein can twist or fold back. If you consider the first class of unfolded proteins, the sequence must be very specific to accomplish the given function, however, for the second class of unfolded proteins I mentioned sequence restrictions would be very minimal. Hence, the statement:
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though often of lower sequence complexity [1] (and hence, easier to evolve via random generation).
is not a generally applicable fact. This point needs to be elaborated upon before becoming a general and basic tenet of "how proteins came to evolve." (i.e. of the different kinds of unfolded proteins, how many are low sequence complexity and what function do these low complexity sequences perform? An unfolded protein domain that provides flexibility is not too hard to generate, sequence-wise compared to say an unfolded protein that generates cooperative oxygen binding.)
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In fact, there is evidence that disordered proteins outnumber ordered proteins, but that the ordered ones represent more resolved structures in the PDB simply because (big shock) they’re easier to crystallize.
What is the evidence for this? What are the statistics of the proteome for folded verses unfolded proteins/domains? (Since "unfolded" is doubtfully a recognized domain due to the probably large number of ways to achieve this state, there should be little sequence homology to give such a prediction of percent unfolded proteins/domains without direct testing on each individual protein, so I'd be interested in knowing how such a calculation has been currently made.) Also, there are many reasons a protein won't crystallize besides the fact that they are unfolded. For example, Kinases are recognized as folded proteins and many have been crystallized, yet some are unable to be crystallized, and the reason is not necessarily because some kinases fold and others do not. First, a crystallized protein does not automatically generate a protein structure, you have to obtain the right kind of protein crystal. An additional factor more obvious than "folded state" would be solubility at high concentrations, but also things like the ability of SF9 or e.coli to handle high expression of the protein, etc. These other factors are so important for "why proteins crystallize," that implying that a large percentage of the proteome is unfolded because the structure of many proteins has not been resolved is completely fallacious (I would hope that is not the argument you are trying to make, although it appears to be.)
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So one possible way for folded proteins to come about is by evolving from functional yet disordered proteins, and in this case there would never be a period of time when there was not a selectable function.
This is a computational issue which relates directly to what I said about speculations. Basically you speculate that deriving function will be relatively easy in all cases of protein formation because function very loosely follows sequence identity. Thus you argue that function can arise very easily from within the sequence landscape. This however needs to be supported by something other than the isolated case of proteins with low sequence complex regions that are unfolded yet functional (of which you do not distinguish between types of unfolded domains and relate their sequence complexity to the functions they perform.) The function of many proteins may be completely impossible without applying folded proteins to the task, we need data to make the distinction. You are taking a small and limited case and trying to apply it globally, which I don't think is reasonable. As I said before, we need hard evidence for these issues, not speculations on possible ways to dream up the evolution of proteins. Unfortunately all I've seen in the debate of evolution vs. intelligent design is speculations because the data is not available. IMO the verdict is still out and may be a long time coming.
Next you posted two papers followed by:
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So both of these papers support the idea that an evolutionary process not only can account for the emergence of protein folds, but that the distribution of folds is a predicted consequence of evolution.
This actually does not follow. The two papers actually show the parity of the evolution of proteins, assuming evolution is true, for the following reason. Paper one discusses the fact that proteins fit into discrete relationships and many proteins utilize similar folds. The second indicates that the proteome only utilizes 10,000 folds. Now, if evolution has an easy time deriving sequences and function is so easy to generate, why is a particular domain saved and used over and over and over? Novel sequences should be so common and easy to generate that there is hardly any relationship between proteins at all, following the previous logic. I admit that it is reasonable based upon this fact alone to say that evolution found what was needed for the first cell and then did the minimal amount of work to generate larger diversity. However, distinguishing this from a designer who carefully generated sequences that uniquely fit each organism in a maximal capacity for optimized function is impossible based upon this fact alone. Adding other arguments generates different conclusions, but I wanted to harp on this (since others have also brought up basically the samepoint on the phylogenies thread.. see I think John Brachts first few posts.) Secondly, the fact that only 10,000 domains are used indicates that evolution somehow had to select through a much larger set of theoretical protein sequences and domains to only end up with 10,000 (which is infintesimal compared to the possible sequences available.) This requires a "theory of discovery" for creating proteins, because only 10,000 are used. Again, we are back to complete speculation saying "well, almost all sequences are functional, therefore evolution was easy" or "only about less than one percent of possible sequences/domains are used and only a small percentage more are even possibly functional, therefore evolution is for all intents and purposes impossible." (I didn't do the math and I don't actually know EXACTLY what percentage these domains represent of the possible sequences, but I'm sure it is quite small.) It is a case of the half empty or half full glass, and metaphysical presuppositions has everything to do with it. I would be quite interested in responses directly to this particular issue (data sets about possible/actualized protein sequences.)
Next you list a model and say:
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I don’t know if this model will last, or even if it can stand up to serious scrutiny right now
I wouldn't think so at all because there is no relationship mentioned here between sequence and functional output. Steps 4 and 5 appear to be a monumental jump from the previous steps, functionally.
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However, once you have a functioning cell, I don’t see any problem with the ability of current theory to account for protein evolution.
I don't see how this follows? Is function somehow easier to come by/ folding easier for proteins once inside a cell? How do cells narrow the relationship between sequence, structure and function?
quote:
[This last reference is at the end here for no real good reason]
1. Proteins 2001 Jan 1;42(1):38-48, Sequence complexity of disordered protein.
quote:
------------------------------------------------------------------------
Intrinsic disorder refers to segments or to whole proteins that fail to self-fold into fixed 3D structure, with such disorder sometimes existing in the native state. Here we report data on the relationships among intrinsic disorder, sequence complexity as measured by Shannon's entropy, and amino acid composition. Intrinsic disorder identified in protein crystal structures, and by nuclear magnetic resonance, circular dichroism, and prediction from amino acid sequence, all exhibit similar complexity distributions that are shifted to lower values compared to, but significantly overlapping with, the distribution for ordered proteins.
------------------------------------------------------------------------
Actually, there is good reason for it in relation to what I was saying. The fact that they lumped all proteins that displayed any type of disorder "sometimes existing in the native state" and found that these proteins displayed "significantly overlapping" order distribution says a lot. I think the analysis would be better if function of the disordered region was taken into consideration. Perhaps then a more general conclusion can be made about unfolded domains and how they widen the relationship between function and structure and sequence.
Thank you for the thoughtful response, and no I probably did not review all the articles you posted in full depth (since I'm not at work and don't have access to the scientific literature at home), so please don't hesitate to elaborate on any points I may have missed from them.
Josh
[ 31. December 2002, 20:08: Message edited by: Josh ]
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