Astrobiology Science and Technology for Exploring Planets (ASTEP)

PI: Krishnamurthy, Ramanarayanan

Comprehensive experimental investigations have been undertaken by the Eschenmoser group towards an understanding of Nature’s choice of the structure type of the natural nucleic acids as the molecular basis of genetic function (Chemical Etiology of Nucleic Acid Structure). A central conclusion from these studies is the notion that Watson-Crick base-pairing is by no means unique to the ribofuranoid oligonucleotide system, but is rather widespread among potentially natural nucleic acid analogs with backbones that contain sugar units different from ribofuranose. Another conclusion to be drawn from this work, one that is forcibly corroborated by the work of others in the field of medicinal antisense-oligonucleotide chemistry, is the notion of a still largely unexplored structural landscape of informational oligomer systems that may contain backbones, recognition elements and linker groups structurally quite different from those known so far. We deem this landscape to contain oligomer systems that have the generational simplicity of potentially primordial systems, primordial in the sense that, from a chemical point of view, they may have had a chance to self-assemble under the chemical and physical constraints of a prebiological geochemical environment. A structurally unconstrained experimental exploration of this landscape with focusing on such potentially primordial members would represent a continuation of the project pursued so far, yet would reach far beyond it, as the target criterion would no longer be the search for function among structural RNA alternatives of a generational complexity similar to that of RNA, but rather a search for generational simplicity among (functional) oligomers, a simplicity that justifies a given system to be deemed potentially primordial. We propose a systematic experimental study of families of such candidate systems, the structures of which are deduced by combining two conceptual strategies, first, a “forward-synthetic analysis” starting from a range of elementary starting materials while obeying rather strictly defined structural constraints of prebiotic chemistry and, second, a qualitative conformational analysis that allows us, as experienced in previous studies, to predict a system’s base-pairing capability with reasonable certainty. What encourages us in such an endeavour are the (unpublished) results of our (still) preliminary experimental studies of oligomers whose backbones are derived from ethylenediamine-, peptoid-, and peptide-based monomers and in which the family of the canonical nucleobases is being replaced by an alternative family of (equally primordial) heterocycles. We have found that oligomer sequences tagged with one of the members of this alternative nucleobase family are capable of cross-pairing with RNA and DNA in four different backbone series. This finding calls for a comprehensive extension of these studies in a variety of
directions.