For this blog entry I wanted to write about one of the talks from the NAI Workshop that I saw on Monday given by Ram Krishnamurty from the Scripps Research Institute on his research into structural alternatives for RNA. The basic motivation of his research is to study the potential of novel oligomer systems to act as informational systems similar to RNA. One of the major goals of Krishnamurty’s team is to systematically synthesize, by chemical methods, potentially self-replicating chemical systems that may have been competitors to RNA in a primordial world. At the conference he presented a system he recently synthesized in which he expected the strands of the molecule to pair well with DNA and RNA as well as with its partner; however, some of the strands failed to bind which led to the discovery an additional criterion for strands that may shed light on why RNA prevailed in the primordial world.
So far this semester, it has come up a lot that before the rise of DNA, RNA acted alone in propagating primitive life. We’ve also explored the idea that, in such an “RNA World”, there would be a fundamental necessity of RNA to act as both a transmitter of information and catalyst of life-sustaining reactions. However, even years of research, the potential for RNA to self-assemble under what are thought to be likely primordial conditions still hasn’t been demonstrated.
In the talk, Krishnamurty presented results they have discovered recently regarding the chemical nature of pre-biotic RNA. The work focused on two pair of oligomers with the diamino and dioxo forms of triazines, and the diamino and dioxo forms of pyrmidines acting as alternative bases. The expectation was that the diamino and dioxo forms of each would exhibit Watson-Crick base pairing, and that the compounds would also bond well with RNA and DNA. It turned out that the diamino triazine paired strongly with RNA and DNA, as expected, but the diaxo triazine paired very weakly. This was strange, but even stranger was that the observations for the pyrmidines was opposite: the dioxo paired strongly, and the diamino paired weakly. This lead to the discovery of a remarkable correlation between whether the base in a synthesized compound bonded will with RNA and DNA or its pair, and the value of its acid dissociation constant (pKa). These results suggest that a base with a pKa value close to that of the base it is to pair with will have weak, if any, bonding, while the team found strong bonding among bases with high differences among their pKa values.
So, the ultimate conclusion of his talk was that the optimal strength of bonding between bases is literally responsible for life as we know it. Bonding that is too weak would prevent self-replication from proceeding, while bonding that was too strong might do the same, because double strands would become too difficult to separate. RNA and DNA exhibit an optimum base pairing strength, and understanding the reasons why are critical to understanding how they arose.
So, Ram and his team initially set out to identify potential RNA alternatives, but what they found was a very interesting new criterion to better understand RNA and DNA and further the search for alternatives or precursors. The pKa itself may not be responsible for the relative bonding strengths of different bases, the results do suggest that pKa differences are a good and relativle convenient indicator for potential bases that will have the proper bonding strength. An interesting time is upon us, where pKa may now be one of the first considerations in work to identify alternative bases.
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