Let’s hear it for the blind watchmaker

The blind watchmaker had a lot of foresight in choosing to use a rather  funky looking amino acid (proline) resembling none of the others.  A lot of kindness was also shown to structural molecular biologists by two of the watchmaker’s henchmen – Burkholderia gladioli and the common daisy.

All appear in a fascinating paper [ Cell vol. 176 pp. 435 – 447  ’19 ] in which the structure and better the mechanism of action of the mitochondrial ADP/ATP translocase, a molecule of some interest since our mitochondria make our body weight of ATP each day and need some way to get it out into the cytoplasm where it is used.

The molecule has quite a job to do, getting the rather large ATP molecule out to the intermembrane space (and thence out to the cytoplasm) without allowing protons to sneak out with it, since it is the proton gradient which is used to power ATP synthase the exquisite machine which makes ATP.   This is quite a trick as no chemical moiety is as small as a proton.

The translocase has two states — one in which it is open to the mitochondrial matrix (called the m-state) and another in which it is open (eventually) to the cytoplasm — called the c-state. In the m-state the cytoplasmic portion is shut, and in the c-state the membrane portion is shut.

The rather wierd looking molecule bongkrekic acid  made by Burkholderia gladioli  https://en.wikipedia.org/wiki/Bongkrek_acid binds to the translocase fixing it in the m-state.  Atractyloside, made by daisies binds to the molecule fixing it in the c-state.  They made life much easier for the structural biologist and cryoEMographers who wrote the paper.

Proline comes in because when placed in an alpha helix, proline’s 5 membered ring structure fixes the alpha carbon so that it is essentially inflexible, meaning that it can’t get into the conformation that the other 19 amino acids can get into when an alpha helix is formed.  Translation — proline is a helix breaker, forming a kink in the helix.

The translocase contains 3 modules of 100 amino acids each of which has 2 alpha helices, one of them containing a proline causing a kink in the helix.  The prolines are in the middle of the helix.  The ATP channel is formed by the 6 helices.

Essentially in the middle of the membrane, the kinked alpha helices form a pivot (fulcrum), so the helices rock back and forth, opening one side while simultaneously shutting the other, permitting ATP to bind near the fulcrum without letting anything else through, when the pivot shifts   — out goes the ATP (without letting protons sneak past).

There is far more beautiful protein chemistry on display.  There is a conserved signature motif Proline x Aspartic acid/Glutamic acid X X Lysine/Arginine at the carboxy terminal end of one of the helices of each other 3 modules — this forms a salt bridge shutting the channel on the matrix side.  Glycine and other small amino acids (alanine) allow close packing of the helices on the cytoplasmic side.

It is unfortunate that the most of humanity doesn’t have the background to appreciate the elegance and beauty of Nature’s solution to the problem.  I say Nature rather than God to be scientifically correct, but it’s elegant chemistry like this that makes it hard for me to accept that it arose by the machinations of a blind watchmaker.

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  • Thanos  On February 11, 2019 at 1:11 pm

    It is unfortunate indeed but what I think is even more unfortunate is most scientists’ (biologists mostly) adherence to the blind watchmaker thesis and the Neodarwinian paradigm in general which in my opinion halts progress and perhaps also leads biomedical research astray.
    Why do you think that so many smart people with deep knowledge of the chemical ingenuity of Nature can delude themselves so much? I’ve been following Derek in the pipeline’s blog for years and as much as I respect his profound knowledge I can’t wrap my head around his inability to see the patent intelligence with which Nature is wrought and instead even mocks such an idea in his posts.

  • luysii  On February 11, 2019 at 10:05 pm

    Thanos: Thanks for commenting — it does take a while for comments to show up on the blog after I approve them. Not sure why

    I’m going to do a new post collecting some old posts on this topic. It is very hard (for me) to accept that the exquisite biochemistry, chemistry and molecular biology being discovered on a nearly daily basis arose purely by chance.

    I don’t have a better explanation however. One can disagree with a paradigm without being required to come up with something to replace it. Michelson and Morley destroyed the ether paradigm in 1887, but its replacement didn’t occur until Einstein’s special relativity in 1905.

  • Thanos  On February 17, 2019 at 8:38 pm

    As far as alternatives to the orthodox paradigm I would single out the so called Natural Genetic Engineering put forward by the molecular biologist James Shapiro which was motivated especially by the recent discoveries of the different functional RNAs and the accumulating understanding of the plethora of complex epigenetic mechanisms. This alas, has received very little attention partly because it was championed by ID zealots and thus got inadvertently stigmatized. and partly due to inherent inertia of the scientific community. I wouldn’t call it a complete theory (nowhere near the status of Relativity which could equally be said of the modern synthesis as well) but I think it’s in the right direction.

    On another note it was remiss of me in my first post to not commend you on the breadth of knowledge you display on this blog. I am a mathematical biologist (still in training) and very seldom do I find (if ever) individuals with deep understanding of both biology/chemistry and mathematics. I would wager this could be the reason why you too, perceive the gaping hole in the “logic” of neodarwinism while most life scientists don’t or won’t.

    Will be looking forward for the new posts on the topic!

  • luysii  On February 19, 2019 at 10:23 pm

    Thanos: Thanks for the kind words.

    Unfamiliar with Shapiro’s work. How about a link.

    I’ve written some about all the new RNA players. Have a look at this https://luysii.wordpress.com/2015/03/22/why-drug-discovery-is-so-hard-reason-26-were-discovering-new-players-all-the-time/

  • Thanos  On February 25, 2019 at 6:00 pm

    Sorry for the late reply, here is a link with some of his selected papers. https://www.thethirdwayofevolution.com/people/view/james-a-shapiro

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