Debate in science…

posted by Kendra

From the Racaniello blog, post May 6th:

The diagram shows amantadine in the M2 channel contrary to suggestions of an allosteric binding site as discussed in BCMP201.

Any thoughts on this in particular or on the existence of “camps” supporting different models in science? Is this sort of division good or bad?

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5 Responses to “Debate in science…”

  1. I think conflict is a good thing. If you think about it, throughout history war has been the driving force for technological development. When your about to be slaughtered you find that extra motivation to create. I think conflicts like this are exciting for others to watch, and I think it also would motivate the proponents of both groups to work harder. Since science is self correcting the best answer will prevail. In addition hybrid models normally result from these arguments anyway.

  2. Just to throw my hat in the ring, when we talked about this in the Proteins course I actually was in the “camp” arguing for the molecule plugging the pore of the channel directly, as opposed to the allosteric model. My reasions were two-fold. First, a molecule such as amantadine, with inherent polarity, will orient itself in lipid-bilayers in a way that places the charged amine pointing towards the negatively-charged heads of phospholipids. This would, in effect, make it very difficult to move that charge to the center of the bilayer to bind this putative allosteric site. Secondly, natural selection doesn’t lie. If a virus is being selected for and which possesses an error-prone polymerase in a large viral population, the most efficient way to get around something will arise. I find it convincing that influenza has mutated the residues around the site at which amantadine has been found. For these reasons I’m favoring the direct binding model, where amantadine is first in solution and will likely be largely soaked up by lipid bilayers, but that a few molecules will find and bind the M2 channel in the opening pore.

    I’m also going to agree that the existence of “camps” in science is good, and I really don’t feel that disagreement and refinement of models in any discipline can be viewed of as “bad”. As was said at the beginning of this semester, science is a self-correcting endeavor, and without disagreement we’d not have refined models that we have today. Now if you’ll excuse me, there are some swan-necked flasks I have to go check to see if the aether’s vital force spontaneously generated some animalcules…..

  3. Kendra Says:

    However, the amantadine-in-pore model group suggested that the amide group would point downwards towards the virus interior, putting it in very close proximity with the conserved histidine residue resulting in positive charges opposing each other (I believe this was brought up by Kevin in our BCMP discussion). Also, the conservation of the C-terminal portion of the channel due to structural constraints imposed by the gating mechanism can explain why mutations occur distally to the putative allosteric site.

    As to the other thing…while I agree that science is self correcting and that models often work themselves out *eventually*…given the reality of limited resources, I find it very frustrating that sometimes egos overrule self-correction: the Science paper getting in the way of the science.

  4. A histidine residue possesses not only the hydrogen coming off of one nitrogen, but also another nitrogen with a lone pair creating a partial negative density which could interact with the positive charge of an amide group. Across four of these residues per pore, that’s a significant amount of complementation, and since histidines should have a certain degree of free rotation, this can’t be discounted. In addition, while the authors of the allosteric site showed that they have a putative site, without other evidence it seems just like a possible artifact of doing this in NMR. While I realize that both X-Ray Crystallography and NMR structural studies can induce bias, the evidence of those residues near the binding site in the X-Ray structure still lend more support. One would assume that, if the allosteric site is the key site, that the mutations would be at the allosteric site, or near the gating site to alter its threshold for opening.

    I agree that there also is limited funding, but shouldn’t interfere with that you pursue a question until there’s a reasonable consensus or a concrete set of data which gives one side a large amount of support. Since this question still is open, I’d argue that the Science paper is helping, not hurting science….especially if it turns out to be the correct hypothesis…

  5. Hmm…the Science paper comment wasn’t in reference to the amantadine debate in particular. You must admit that there have been times in history when scientists with a correct model supported by good data have been unable to (or have found it difficult) to publish because they go against the prevailing model. While I must admit if I were a peer reviewer, if someone submitted a paper that went against evolution or general relativity or something, then that would probably be a problem….but all I’m trying to say is that sometimes I feel like biologists are too quick to adhere to the model instead of the data.

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