Is science sometimes in danger of getting tunnel vision? Recently published ebook author, Ian Miller, looks at other possible theories arising from data that we think we understand. Can looking problems in a different light give scientists a different perspective?

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Archive for March, 2015
Two posts ago, I issued two challenges for readers to try their hand at developing theory, and so far I have received a disappointing response. Does nobody care about theory? Anyway, my second question was, why did nature choose ribose? Recall that ribose is not the easiest sugar to make, and in the Butlerov synthesis, under normal conditions essentially no ribose is made. However, that may be misleading, as there are other options. One that appeals is, providing pH 9 or more is reached, silicates dissolve slightly, and catalyse the condensation of glyceraldehyde and glycolaldehyde to form pentoses, and the furanose form is favoured (Lambert et al. 2010. Science 327: 984-986). This strongly favours ribose.
 
However, even if we can find a way to make ribose, it is inconceivable that we can do that without making other sugars, so why did nature choose ribose? One answer is, it is the most suitable, but that begs the question, why? It is certainly not that it alone can lead to duplexes once the strand is made, because it has been shown that duplexes based on xylopyranoside or arabinopyranoside, or even ribopyranoside have better duplex binding, and xylose and arabinose are easier to make.
 
I think the answer lies in part in what is an essentially forgotten paper by Ponnamperuma et al. 1963 (Nature 199: 222-226.) What Ponnamperuma et al. did was to take adenine, ribose and phosphate in aqueous solution, then they shined hard UV light (wavelength about 250 nm) on it. Products included adenosine and adenosine phosphates, including adenosine tripolyphosphate. This was quite a stunning achievement, but it leaves open the question, why did it work? Before addressing that, however, we might see why this has been forgotten, apart from the issue of who reads the literature before computer searching? There is a serious flaw in this being the cause of life, and that is that it is almost impossible to conceive of an atmosphere that will remain transparent to such short wavelength UV. For example, water gets photolysed to oxygen, thence to ozone, which screens out the hard UV. If there are reducing materials there, you get a haze like that on Titan, and again, the hard UV gets screened out.
 
My recommended way of forming a theory is to ask questions, and in this case, the question is, why does light make the phosphate ester? The adenine is clearly absorbing the photon, and one can see that the link between adenine and ribose may be photocatalysed, but what happens next? All bonds in the ribose are σ bonds, so there should be no extension to the excited electronic state. The next question is, how can one make phosphate esters? This is slightly easier: if you heat a hydroxyl and a phosphate with a hydroxyl to about 200 degrees C, water is eliminated and we get the phosphate ester.
 
This suggests the answer to the problem should lie in radiationless decay of the excited state, where the energy is dissipated in a sequence of vibrational energy levels decaying to the ground state. We now see that a vibrationally excited hydroxyl could form an ester if it had the same kinetic energy as a hydroxyl at 200 degrees C. If that is the case, we now see why nature chose ribose: the furanose is more flexible, and the 5-hydroxyl on a furanose will behave a little like the end of a whip. Ribose is the only sugar that forms a reasonable fraction of itself in the furanose form in aqueous solution. Now, adenine cannot be the primary absorber originally, but there is another option, and that is, given the appropriate reduced rocks, if the cell wall hydrocarbons contain dissolved porphyrans, or some similar material, the absorption could be through them.
 
Which brings us to an experiment that could be carried out. Make micelles or vesicles from hydrocarbon alcohols with phosphate esters as the surfactant, and have them with dissolved porphyran, and ensure the water within contains phosphate, adenine, and a mixture of ribose, xylose and arabinose. The prediction is that adenosine phosphates will be formed, but the xylose and arabinose will not participate in forming phosphate esters. If that is true, it is fairly clear why nature chose ribose: it is the only sugar that works
 
Thus we have a clear possible explanation, and an experiment that would confirm of falsify it. The question now is, will anyone carry it out?
Posted by Ian Miller on Mar 23, 2015 12:17 AM GMT
So, my theory challenge, with three weeks to think about it, got no responses. Perhaps nobody is reading these posts. Perhaps nobody cares about theory. That would be ugly. Perhaps the problems were too hard. Really? Anyway, first, a review of where science is at the moment: www.ncbi.nlm.nih.gov/pmc/articles/PM2857173/  My argument is that none of this review answers the question, but it does give a very large number of references. Given that there was this much activity that failed, maybe this challenge was unnecessasrily hard, but let me give you my proposal on how homochirality occurred.

The way to form theories is to ask questions, and in this case ask why did nature choose to be homochiral, given that it wasted half its resources. Why would not some other life form use both, and gain competitive advantage? The obvious answer is that nature chose homochirality because it had to, i.e. if it did not become homochiral, there would be no life. Now, most of what life requires does not demand homochirality. Sources of chemicals could in principle be of any chirality, light is not chiral, energy transport (ATP) depends on the tripolyphosphate, however there is one part where chirality is critical: reproduction. Reproduction occurs when a strand of nucleic acid allows its complement to form as a second strand, where it forms a duplex (double helix). When the duplex separates later, both single strands can grow further new strands, which in turn can form two new duplexes. Note that the helical nature is imposed by the chirality of C-4 on the ribose. The single strand does not have to form a helix, but the two strands, to be intertwined, must both form a helix with the same pitch.

The second strand does not grow by itself. What must happen is that the second strand forms by the complementary bases, with 5-phosphated ribose attached, form hydrogen bonds with their complementary base on the nucleic acid strand. It is now loosely attached by the few hydrogen bonds, and either the required 3-hydroxyl is close to a 5'-phosphate or it is not. If it is, then the ester bond can form, given an impulse from somewhere to overcome the activation energy. If the ribose chirality is correct, esters can form; if it is not, the two sites never come close enough, no ester is possible, and the base eventually wanders off and sooner or later the correct chirality will appear and the duplex grows. Think of a nut and bolt - you cannot make this work if every now and again the thread changes from left handed to right handed pitch. If there is a wrong chirality on the first strand, no duplex can form either, and the impulse required to bring the groups together is now also the impulse required to unravel the duplex.

RNA strands can form loops held together by magnesium ions and these emerging ribozymes can act as catalysts, and these can hydrolyse exposed RNA strands. It may be that it can preferentially solvolyse parts where the pitch chages. Some work is required to validate that piece of speculation, neveretheless, the duplex is at a lower energy than two single strands, so eventually we expect a double helix to form, especially if errors in the chain can be solvolysed.

Once you have a reproducing chiral molecule that can act as a catalyst, then it uses all the resources more effectively than any other option, and when it catalyses syntheses, it synthesises chiral entities. Thus it is RNA that is critical for homochirality; it is the only molecule that can arise naturally, sort itself out, then reproduce. Reproduction ensures that it prevails. Whether it chooses D for sugars and L for amino acids would be pure chance on this interpretation, and it would be predicted that half of alien life would choose the other.

Is that unnecessarily difficult?
Posted by Ian Miller on Mar 9, 2015 12:23 AM GMT
One of the themes I have persisted with in these posts is that in chemistry, thinking about theory is either dead or in terminal decline. Prove me wrong!
 
In my last post, I offered a challenge to readers, specifically, can you provide answers to:
1.     Why did nature choose ribose for nucleic acids?
2.     How did homochirality arise?
So far, I have no guesses/inspired answers. Come on! Assuming someone is actually reading these posts, either they don't care or it is too difficult. Now, surely you are not going to concede that I can work out more than you can? So, is anyone going to try?
 
My first answer next week.
Posted by Ian Miller on Mar 1, 2015 8:38 PM GMT