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Author
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Topic: John G. Watterson on Molecular Machinery
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James A. Barham
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Member # 50
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posted 05. June 2002 08:14
I have recently encountered the fascinating work of John G. Watterson, which I would like both to publicize and to solicit feedback on.
In a nutshell, he is arguing from very simple and seemingly irrefutable empirical grounds to the necessity for coherent action at the mesoscopic level in order to explain cellular function. His proposed mechanism for coherent action is ordered water (similar to Gerald Pollack's ideas). But even if the positive suggestion is not right, it seems to me that the negative critique of the conventional viewpoint is devastating. Here is a typical passage from the most recent paper of his that I have been able to locate.
After a brief discussion of the well-known protein folding problem, he continues as follows:
"Yet, the main point about proteins is not their puzzling stability, but that they function as molecular machines (enzymes). They are the nanomachines of living systems, manipulating energy and material within the cell in an apparently purposeful way. . . .
"The problems arising from applying statistical principles to these nanomachines deepens when we take the cytoplasmic environment of the subcellular world into consideration. In the popular models describing how these machines work, the shape and stability of the protein is taken for granted as fixed properties. Biochemists are, in the main, unaware of the thermodynamic arguments against this assumption, and so see no difficulty in using it. In addition, the aqueous medium is too often ignored, so that the component parts of their models are depicted as moving in empty space. When we fill this space with water however, modelling difficulties arise which are the direct consequence of the facts, that the solvent has the same density as the moving parts and it also possesses the same thermal energy. In other words, enzymic processes should be depicted as taking place within an inert medium whose chaotic bombardments disperse their energies and hinder their progress. These processes therefore, should be shown to have control over their environment, because, in order that enzymes convert chemical energy into work with certainty, they must cycle through a series of precise physical steps, which cannot tolerate disruptive collisions from outside. But such models would have little chance of success, since the energy source, usually the phosphate bond of ATP mentioned above, is equivalent to 5, 10 or at most 20 H-bonds, and so could hardly be used to tame the violent surroundings of many hundreds of independently acting water molecules, let alone also then be used for the task at hand. This is simple arithmetic, it is not a sophisticated thermodynamic argument.
"However, the nanomachines of life are conceptualized by biochemists in the absence of water. For example, the much discussed molecular motors of the myosin (Cooke, 1986), dynein and kinesin (Vale, 1992) systems, which achieve the transduction of energy gained from ATP hydrolysis into the mechanical work of vectorial motion, are depicted in terms of tight gripping actions and stiff lever-type movements of solid members about rigid hinges in free space, reminiscent of the inner workings of our car engines. But the network of strong covalent bonds that hold together the metals of our man-made machines have not been located in the cell. On the contrary, metabolic machinery is composed of the soft gel material of the cell interior, and so we need a fundamentally new concept to deal with the production of force in this condensed watery environment. I believe this new concept is one of participation and cooperation of the solvent in the functioning of molecular machines. To achieve this, the new concept must supplant the random collisions of traditional statistical theory with a coherent action that operates on the mesoscopic level. We need a new principle at this intermediate hierarchical level in order to explain how our nanomachines achieve the two-way interconversion of chemical energy and physical work, i.e. how they transduce energy between the metabolic molecular level below and the physical macroscopic level above.
"The traditional view of liquid water as a structureless chaotic medium (Finney, 1979), does not allow the possibility of it being part of an energy transducing machine. Indeed, in such a view, its role in the production of directed action can only be a disruptive one. On the other hand, the cluster model presented in this work, provides us with an entity which has the size in the mesoscopic range along with proteins. This model is based on the idea that the making and breaking of H-bonds between individual water molecules is co-operative, so that the formation of bonded networks, their build-up and break-down, are on-going processes travelling through the liquid medium like successive waves of polymerization and depolymerization reactions (Watterson, 1981). In this water-cluster model, clusters, although constantly changing, are at any instant held together internally by an unbroken linkage of intermolecular bonds. This means that the molecules exert tension on one another, although this tension obviously cannot extend beyond a break in their interconnections. Therefore, over spatial dimensions larger than the cluster size, pressure and not tension, operates throughout the liquid (Watterson, 1991). In this picture, these basic opposing forces do not cancel one another, but co-exist on different hierarchical levels: tension on the molecular scale below the size of the interconnected networks, i.e. inside the clusters, and pressure on the macroscopic scale in volumes larger than the cluster size (Watterson, 1995a). The possibility that intermolecular forces are tensile, removes the destructive randomizing action of collisions. On this basis, we can now explain how molecular machines are constructed out of their soft watery components, and how they can function in such an environment without the need of the steel and concrete of our man-made world."
(John G. Watterson, "The Pressure Pixel---Unit of Life?," BioSystems, 1997, 41: 141--152; pp. 143--144).
Searches have turned up very little on this theory, while a couple of conversations with colleagues have revealed that Watterson seems not to be taken seriously. Yet, what he is saying is very simple and makes perfect sense, so far as I can see.
Could I ask those of you who know more physics and more biology than I do to please comment? Thank you very much.
(Also, if anyone can put me in touch with Professor Watterson, I would be very grateful.)
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Art
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posted 05. June 2002 18:54
Hi James,
At the end of your post, you remarked: quote:
Searches have turned up very little on this theory, while a couple of conversations with colleagues have revealed that Watterson seems not to be taken seriously. Yet, what he is saying is very simple and makes perfect sense, so far as I can see.
Not knowing anything more than you posted, I would hazard a guess that Watterson's depiction of the watery milieu of the cell, and of the possibility of meso-scale ordering, is probably hopelessly confounded by the realization that he ignores things such as highly charged as well as merely polar solutes. I don't think the idea would hold up very well in, say, a 250 mM solution of sodium chloride.
This is compounded by the fact that Watterson's representations of the perceptions of biochemists vis-a-vis their views of the environments in which enzymes act are very, very wrong.
Here is a useful tutorial that may be helpful (if for no other reason than to dispel some of Watterson's notions about biochemists).
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James A. Barham
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Member # 50
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posted 06. June 2002 07:46
Art:
Thanks very much for your post, and the great link. The tutorial looks excellent, and I shall study it with care.
I wish that Watterson were here to defend himself, since I am a poor substitute, but as I understand it, the claim is that regularities in the charges on the protein surfaces are the forces that are hypothesized to create the ordered water, thus taking electrostatic forces explicitly into account. (Admittedly, this was not apparent from the extract I posted.) So, naturally, no such effect would be found in a simple saltwater solution.
But what about the more general point that the water must be considered an integral part of protein function?
I am discovering that this is a more widespread view than I realized at first.
For example, Avraham Oplatka of the Weizmann Institute in Rehovot, Israel, claims that our fundamental understanding of muscle contraction is completely wrong ("The Rise, Decline and Fall of the Swinging Crossbridge Dogma," Chemtracts--Biochemistry and Molecular Biology, 1996, 6: 18--60). He further argues that (a) there is a univeral mechanism underlying all cellular motion in all life forms, and (b) it is fundamentally tied to directed water propulsion off of protein surfaces.
Interestingly for this forum, in a separate paper, Oplatka writes that the bacterial flagellum should be viewed, not as an outboard motor, but as a water turbine. Apparently, there is no good theory of how the proton flow (according to the chemiosmotic theory) is converted into mechanical motion at the "rotor/stator" structure in the bacterial flagellum, and Oplatka says that is because that is not what is happening at all! ("Do the Bacterial Flagellar Motor and ATP Synthase Operate as Water Turbines?", Biochemical and Biophysical Research Communications, 1998, 249: 573--578)
Now, this does not affect the basic argument of Behe and other ID supporters, because the structures still cannot be accounted for by "chance", no matter how they operate.
Still, I find it fascinating that all sides assume that these structures operate in a fashion analogous to man-made machines (i.e., with forces applied externally onto rigid and passive structures conceived of as a set of arbitrary "boundary conditions"), when the actual evidence for this assumption is apparently flimsy to non-existent!!
So, I think that what Watterson, Oplatka, Gerald Pollack, and others are saying is of the very greatest importance for our concerns here at ISCID. (Unless, of course, they are simply wrong!)
[ 06 June 2002, 08:17: Message edited by: James A. Barham ]
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Art
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posted 06. June 2002 23:15
Hi James,
Just a couple of points for now.
You said: quote:
But what about the more general point that the water must be considered an integral part of protein function?
This is really no big mystery, IMO. Maybe the point is not stressed in the more popular press, but I know I was taught about water in biochemical systems pretty early in my education. The subject extends from the roles of water in hydrophobic interactions, to any of a number of acid-base catalysis mechanisms, to even more fascinating subjects. Which causes me to lapse into brief reminiscence.
One of the more interesting and enjoyable meetings I have ever attended was a Nucleic Acids Gordon COnference in the early 1990s. The absolute highlight of the meeting was the session on structure - sitting in near total darkness as slide after slide of amazing protein-DNA structures were displayed and discussed. The point I remember most about the session was the demonstration- direct viewing, essentially - of single immobilized water molecues that formed essential parts of the interfaces between protein and DNA. This was at once amazing and dismaying - amazing because it was (and still is, for many people) assumed that protein-DNA contacts were between amino acid and nucleic acid, and dismaying because it introduced an almost insurmountable problem for the prospects of being able to predict DNA binding specificities of proteins from first principles.
So, the bottom line for me is that water is not really ignored, but rightly recognized as a pervasive and multifunctional player in biochemical systems.
You also said (snipping a lot, and focusing on the second issue I would like to remark on): quote:
Apparently, there is no good theory of how the proton flow (according to the chemiosmotic theory) is converted into mechanical motion at the "rotor/stator" structure in the bacterial flagellum, and Oplatka says that is because that is not what is happening at all! ("Do the Bacterial Flagellar Motor and ATP Synthase Operate as Water Turbines?", Biochemical and Biophysical Research Communications, 1998, 249: 573--578)
I would disagree with this. While flagella are usually not explicitly mentioned in reviews of the ATPase, there are many theories (or, maybe better put, many variants of a general theory) for such processes. The literature is voluminous and very time-consuming; however, because of other novel aspects of his work, I would recommend reading some of Peter Dimroth's articles on the subject. For example: quote:
* Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4735-7.
Energy transduction in the sodium F-ATPase of Propionigenium modestum.
Dimroth P, Wang H, Grabe M, Oster G.
Mikrobiologisches Institut, Eidgenossische Technische Hochschule, ETH-Zentrum, Schmelzbergstrasse 7, CH-8092 Zurich, Switzerland.
The F-ATPase of the bacterium Propionigenium modestum is driven by an electrochemical sodium gradient between the cell interior and its environment. Here we present a mechanochemical model for the transduction of transmembrane sodium-motive force into rotary torque. The same mechanism is likely to operate in other F-ATPases, including the proton-driven F-ATPases of Escherichia coli.
I wish Duane Salmon were here to elaborate on this subject. He had some interesting perspectives.
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kyle7
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posted 07. June 2002 01:42
James,
You say the following:
quote:
Still, I find it fascinating that all sides assume that these structures operate in a fashion analogous to man-made machines (i.e., with forces applied externally onto rigid and passive structures conceived of as a set of arbitrary "boundary conditions"), when the actual evidence for this assumption is apparently flimsy to non-existent!!
I would say that the underlying principles that explain how biological systems work are based on physics -- though fundamentally more advanced compared with our engineered systems. You seem to say that there is an unknown quality about biological systems (an ID ingredient?). Am I understanding you correctly?
We can analyze the bacterial flagellum purely based on the gyrations made by the flagellum and determine the energy required to produce the locamotion and the expected velocities and trajectory of the bacteria. The missing information is the process of energy conversion -- though this may be known to some degree. From an engineering perspective, I don't find anything different from our systems that we design (e.g. propulsion systms), except the complexity. Within a short time, I expect that we will design similar devices that will be put into the blood stream. These devices will take pictures of arteries, unclog arteries, and selectively deposit medicine throughout the body.
CSI, Complex specified dynamics, and complex specified application of energy all point to an ID agent. Natural causes do not explain biological systems. These are some of my reasons for being an ID proponent.
[ 07 June 2002, 01:50: Message edited by: kyle7 ]
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James A. Barham
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posted 07. June 2002 09:05
Art:
Thanks very much for the Dimroth reference. I will look it up as soon as possible. This is exactly the kind of feedback I was looking for!
Of course, I don't pretend to be able to adjudicate between quarrels like those between Oplatka and Dimroth. What I wish is that they would explicitly critique each other's theories, so that a bystander could get a better sense of the issues involved, and where the weight of the empirical evidence currently lies. Maybe there are other references out there that do just this? If not, someone should organize a conference to bring the two viewpoints into direct contact with each other!
Kyle7:
I am attracted to theories like Watterson's, Pollack's, and Oplatka's, because I believe some kind of global coherence is required to explain the massive coordination of functional action in the cell. The fact is, we simply do not understand yet how the cell really works. It is clearly not enough to simply enumerate the "mechanistic" links in the chain. There has to be a way to account for, not only the origin of the whole chain, but the way it actually operates as an integrated whole in real time.
There are a lot of people working on this problem, but they are not really in touch with each other, it seems. There does not seem to be a coordinated effort to counter the mainstream, genocentric, Darwinian, reductionist viewpoint. Or if there is, I am unaware of it. So what I am trying to do is piece one together from the bits and pieces that are out there. Every day, some new physical approach is coming to my attention.
For example, there is a wonderful paper by Howard R. Petty and Andrei L. Kindzelskii entitled "Dissipative Metabolic Patterns Respond during Neutrophil Transmembrane Signaling," PNAS, 2001, 98: 3145--3149, which argues that cell functionality is essentially a matter of low-energy signaling (which lots of people would agree with), which in turn is essentially a matter of transformations on patterns of oscillation of standing waves in the cytoplasm. If I understand them correctly, Petty and Kindzelskii are trying to do directly for the cell what Richard Gordon (The Hierarchical Genome and Differentiation Waves, Singapore: World Scientific, 1999) is trying to do for embryological development.
In short, what I am trying to say is that there seems to be an explosion of work going on right now that is attempting to get at the underlying physical principles that might account for the global coherence of life, in a way that is fundamentally different from the way that manmade machines work. On this view, the teleology of life is intrinsic to the matter of life, not extrinsically imposed from the outside, by either a supernatural designer or an anthropomorphic Darwinian "Bricoleur."
Of course, even if I am right and there is an intrinsic dynamics of the living state that gives rise to natural teleology, the Darwinian reductionists will certainly try to say that that is what they meant all along. Just more "mechanism," in other words. But I don't think they'll get away with it this time.
There is a great article in the latest issue of Philosophy of Science by Stuart Glennan ("Contextual Unanimity and the Units of Selection Problem," 2002, 69: 118--137), which, in spite of its rebarbative title, is quite interesting and pertinent to our debates here at ISCID.
Glennan makes the same point (albeit more elegantly and to a much wider audience) that I have been making in my own work for the past 12 years. Namely, selection theory presupposes the functional organization of life, and so cannot pretend to explain it.
Here is what he says:
"Fitnesses in general are properties of types, but evolution ultimately occurs as a result of the differential reproductive success of individual organisms. The success (or lack thereof) of indivdiuals in turn is caused by the various traits they possess. This fact is not meant to suggest that it is inappropriate to talk of evolution of genotypes. Evolutionary explanations are meant to explain changes in the frequency of genotypes and phenotypes. However, we must get the explanatory order correct. We explain the fitness of a genotype by reference to the reproductive success of individuals having that type, rather than explaining the reproductive success of the individual by reference to its instantiating a genotype. One genotype is fitter than another because on average the individuals that are instances of that type are more reproductively successful than another" (pp. 135--136).
In short, the theory of natural selection explains nothing at all, because it simply assumes the very thing that needs to be explained---the teleological success of living processes. Furthermore, mechanistic explanations are also inherently incomplete and incapable of explaining the overall teleological order of the cell. So, that leaves either a supernatural designer or a sui generis physics of the living state as the two possible explanations. It seems to me that the evidence for the latter is now growing by leaps and bounds.
[ 07 June 2002, 09:12: Message edited by: James A. Barham ]
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Mark
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Member # 888
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posted 04. October 2003 12:54
James,
Watterson's comments reminded me of some writings of Mae-Wan Ho, who places tremendous emphasis on the various functions played by water, not only within the cell but throughout an entire organism.
For example Biology of Free Will
Ho goes so far as to call an organism a "polyphasic liquid crystal." She includes many references in her article, relating to protein and enzyme function, that may be of interest.
A sample quote:
quote:
Recent studies have also revealed that energy mobilization in living systems is achieved by protein or enzyme molecules acting as "flexible molecular energy machines" (see Ho, 1995a), which transfer energy directly from the point of release to the point of utilization, without thermalization or dissipation. These direct energy transfers are carried out in collective modes extending from the molecular to the macroscopic domain. The flow of metabolites is channeled coherently at the molecular level, from one enzyme to the next in sequence, in multi-enzyme complexes (see Welch and Clegg, 1987). At the same time, high voltage electron microscopy and other physical measurement techniques reveal that the cell is more like a `solid state' than the `bag of dissolved enzymes' that generations of biochemists had previously supposed (Clegg, 1984). Not only are almost all enzymes bound to an intricate "microtrabecular lattice", but a large proportion of metabolites as well as water molecules are also structured on the enormous surfaces available. Aqueous channels are now thought to be involved in the active transport of solutes within the cell in the same way that the blood stream transport metabolites and chemical messengers within the organism (Wheatley and Clegg, 1991). Joseph Needham (1936) and his colleagues were already aware of all that some sixty years ago.
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Brad Herp McFall
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posted 04. October 2003 16:29
The issue seems to be one of HOW? - how can the biology 'program' (teleomatics of teleology if you will) the "forces" should such actually exist??
In other words, my guess is, that the detracting or distorting negatively intended similar art will ultimately be found to based on the claim that even if some directums between water and proteins happened by chance (or by God) that 1) scientists already understood the process and/or 2) there is no known programmer organically ordering the design Watterson proposed.
If one wishes to affirm the design then one simply needs to construct a "dissolvable" programmer that can be inserted into flesh and carry out at the same time the proposed forces that are being coordinated by Neton's third law junction functionality functionally but in community removing in real time the central force or point of contact so as to reliquish program control completely to the organic programmer should such exist which will's"" some kind of visible biological output consequent and in summary that the desgin team makes available for humans to discern when (if) a consensus is to be reached about the truth claims of the theory. If such was not just a hypothetical then it would have been shown both, that scientists did not understand it (Watterson himself also) at every instantiation and secondly that teleomatics is not dominating teleology. My educated guess was that if this experimental philosophy was funded to this kind of result that Wolfram's notions of computational irreducibility (chapter 11 in A NEW KIND OF SCIENCE by Stephen Wolfram 2002) would have been shown to have in similiar time frames abdicated or abducted more soma than any genetic rendering of his notions in biology allow. But that is just me. No one person = "experimental philosophy".
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Nel
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posted 05. October 2003 16:11
Art writes:
quote:
I would disagree with this. While flagella are usually not explicitly mentioned in reviews of the ATPase, there are many theories (or, maybe better put, many variants of a general theory) for such processes. The literature is voluminous and very time-consuming; however, because of other novel aspects of his work, I would recommend reading some of Peter Dimroth's articles on the subject. For example:
* Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):4735-7.
Energy transduction in the sodium F-ATPase of Propionigenium modestum.
The model referred to by Art for the motor has been pretty much refuted by experiments such as this:
Berg, H.C. (2003). The Rotary Motor of Bacterial Flagella. Annu. Rev. Biochem., 121801-161737.
[ 05. October 2003, 16:29: Message edited by: Nelson-Alonso ]
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Art
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posted 05. October 2003 19:04
Nelson, I have no idea what you are talking about.
First apologies for the reference to Dimroth's paper - its actually in vol. 96, pp 4924–4929. In the abstract to the paper, Dimroth states: quote:
"The F-ATPase of the bacterium Propionigenium modestum is driven by an electrochemical sodium gradient between the cell interior and its environment. Here we present a mechanochemical model for the transduction of transmembrane sodium-motive force into rotary torque."
Berg, in the abstract to his review, states: quote:
"Flagellated bacteria, such as Escherichia coli, swim by rotating thin helical filaments, each driven at its base by a reversible rotary motor, powered by an ion flux."
Dimroth's model involves the coupling of transmembrane ion fluxes to the generation of rotary motion (that may be used for ATP synthesis, flagellar motion, or other things). Berg's review has nothing that disagrees with Dimroth, and I suspect that the general idea put forth by Dimroth has been folded into the models for coupling of ion fluxes with flagellar motion.
I don't know what your point is, Nelson, but Berg most definitely does not refute Dimroth, and his review does nothing to argue against my broader point, which was (and is, I suppose) that Jame's statement ("Apparently, there is no good theory of how the proton flow (according to the chemiosmotic theory) is converted into mechanical motion at the "rotor/stator" structure in the bacterial flagellum") is not a good representation of the current state of the field.
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Nel
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posted 06. October 2003 22:33
Art,
I was referring to the bacterial flagella motor model of Elston et. al. I thought you were referring to that. As to the model in the paper, I think they assume that the proteins don't undergo large conformational changes, wherease Fillingame et. al. make a case for large conformational changes, not found in the Dimroth model.
[ 06. October 2003, 22:41: Message edited by: Nelson-Alonso ]
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Grape Ape
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posted 07. October 2003 12:56
James writes:
quote]I wish that Watterson were here to defend himself, since I am a poor substitute, but as I understand it, the claim is that regularities in the charges on the protein surfaces are the forces that are hypothesized to create the ordered water, thus taking electrostatic forces explicitly into account. (Admittedly, this was not apparent from the extract I posted.) So, naturally, no such effect would be found in a simple saltwater solution.
[/quote]
I think Art's point is that Watterson (ironic name, eh?) isn't taking polar solutes into account when he argues that the water will have a profound effect on the ability of an enzyme to function. For example, when he says this:
"But such models would have little chance of success, since the energy source, usually the phosphate bond of ATP mentioned above, is equivalent to 5, 10 or at most 20 H-bonds, and so could hardly be used to tame the violent surroundings of many hundreds of independently acting water molecules, let alone also then be used for the task at hand. "
He doesn't seem to be accounting for the fact that water will in many cases preferentially bind to charged ions or other solutes, thus lowering the effect it will have on a protein. In other words, they're not "independently acting" as he seems to assume. But maybe I've misunderstood him.
In general, I think he's setting up a kind of strawman by claiming that biochemists have ignored water, protein flexibility, etc. i have always been taught that these things were of major importance, but in many cases we don't yet know how each of them affects protein function. The simplified models that Watterson criticizes are simplified for a reason, and that's simply to show the general behavior of an enzyme with its substrate without going into specifics. It's quite common to use an over-simplified model when a more complex one can't be constructed.
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Nel
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posted 09. October 2003 01:25
Grape Ape writes:
quote:
He doesn't seem to be accounting for the fact that water will in many cases preferentially bind to charged ions or other solutes, thus lowering the effect it will have on a protein. In other words, they're not "independently acting" as he seems to assume. But maybe I've misunderstood him.
Yes water will bind to things. But his point is all about thermal motion. I think Watterson's point is that, the mechanism of things like myosin comes to mind, it's like walking. When the first leg takes a step it has to break all these water molecules and it has to have the energy to do it. Watterson is expressing doubt that these things have the energy to do it.
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Rex Kerr
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posted 09. October 2003 05:56
Watterson apparently doubts that a fixed energy change of, say, 10kT is enough to cause a conformational change against the background of dozens or hundreds of (3/2)kT collisions.
Saying "there is no way" is no substitute for doing the statistical mechanics. Were he to calculate it out, I think Watterson would be surprised.
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