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Derek Lowe The 2002 Model

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Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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July 7, 2009

What's So Special About Ribose?

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Posted by Derek

While we're on the topic of hydrogen bonds and computations, there's a paper coming out in JACS that attempts to answer an old question. Why, exactly, does every living thing on earth use so much ribose? It's the absolute, unchanging carbohydrate backbone to all the RNA on Earth, and like the other things in this category (why L amino acids instead of D?), it's attracted a lot of speculation. If you subscribe to the RNA-first hypothesis of the origins of life, then the question becomes even more pressing.

A few years ago, it was found that ribose, all by itself, diffuses through membranes faster than the other pentose sugars. This results holds up for several kinds of lipid bilayers, suggesting that it's not some property of the membrane itself that's at work. So what about the ability of the sugar molecules to escape from water and into the lipid layers?

Well, they don't differ much in logP, that's for sure, as the original authors point out. This latest paper finds, though, by using molecular dynamic simulations that there is something odd about ribose. In nonpolar environments, its hydroxy groups form a chain of hydrogen-bond-like interactions, particularly notable when it's in the beta-pyranose form. These aren't a factor in aqueous solution, and the other pentoses don't seem to pick up as much stabilization under hydrophobic conditions, either.

So ribose is happier inside the lipid layer than the other sugars, and thus pays less of a price for leaving the aqueous environment, and (both in simulation and experimentally) diffuses across membranes ten times as quickly as its closely related carboyhydate kin. (Try saying that five times fast!) This, as both the original Salk paper and this latest one note, leads to an interesting speculation on why ribose was preferred in the origins of life: it got there firstest with the mostest. (That's a popular misquote of Nathan Bedford Forrest's doctrine of warfare, and if he's ever come up before in a discussion of ribose solvation, I'd like to hear about it).

Comments (9) + TrackBacks (0) | Category: Biological News | In Silico | Life As We (Don't) Know It


1. Morgan on July 7, 2009 11:17 AM writes...

If you insist on the relevance of Nathan Bedford Forrest to RNA formation, does that make the retrovirus the natural mechanism for "keepin' up the skeer?"

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2. Hap on July 7, 2009 12:01 PM writes...

No - I think they're the avatars of "All's fair in love and war, you know."

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3. emjeff on July 7, 2009 12:08 PM writes...

Fascinating topic, Derek. Thanks

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4. rhodium on July 7, 2009 12:57 PM writes...

There is a related property of cholesterol. Lanosterol, or other intermediates on the way to cholesterol, cause lipid membranes containing the sterols in the biosynthetic pathway to become less and less leaky. Removing and moving those methyl groups, and the other modifications that go into forming cholesterol, may be driven by the specific properties cholesterol imparts to lipid bilayers (work done by Konrad Bloch).

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5. David on July 7, 2009 2:11 PM writes...

I haven't read the JACS paper yet, but take a look at this if you get a chance:

Eschenmoser, A., The TNA-Family of Nucleic Acid Systems: Properties and Prospects. Origins of Life and Evolution of the Biosphere, 2004. 34: p. 277-306.

In short, there are interesting kinetics and energetics involved, not just base pairing, but the ability to differentially pair parallel vs. antiparallel.

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6. partial agonist on July 7, 2009 2:19 PM writes...

You would think that the extra amount of stability gained in hydrophobic environments due to the H-bond network would show itself in the determination of the experimental log P, wouldn't it?

Real-life log P does depend upon conformation and dipole effects, which straight atom-additivity algorithms miss in calculating log P. I've seen this with different diastereomers having much different experimental log P values due to their unequal conformational preferences, whereas calculations of course suggested there would be no difference.

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7. John on July 8, 2009 11:04 AM writes...

I think the big bad-ass phosphate on the RNA polymers is more than enough to keep ribose inside a lipid bi-layer.

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8. Moody Blue on July 8, 2009 11:06 AM writes...

Good point. The original authors did use cLogP to correlate with permeability (observed) and found ribose an outlier - for a good reason. Like with any "predicted" values of properties, you've got take them with a pinch of salt. I am not sure if either the atom additivity method or fragment based method are "taught" to recognize intramolecular method H-bonds. I have seen with some compounds such intramolecular H-bonds can decrease (already low) aqueous solubility and can enhance crystallization.

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9. Alastair on July 10, 2009 8:04 AM writes...

It's great to read a post about this subject as it's an area I used to work in. The origin of RNA and coded peptides is a subject only organic chemistry is likely to solve, and there's lots of interesting organic chemistry published in the field, particularly from the groups of Eshenmoser at ETH and John Sutherland in Manchester.

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