A Search for Structural Alternatives of RNA

Abstract

This account describes a search for potentially primordial informational oligomers; the work is the direct outcome of the research program that was initiated by the Eschenmoser group —at ETH Zürich about 20 years ago and was continued at The Scripps Research Institute since 1996— in order to understand the chemical basis on which nucleic acids were chosen by nature as the molecular foundation of its genetic apparatus. The investigation began with the study of the base-pairing properties of structural alternatives of nucleic acids —constructed from different sugars (hexo- & pentopyranoses and tetrofuranose) retaining the canonical nucleobases and phosphates. The outcome from these studies led to the conclusion that Watson-Crick type base-pairing is not unique to RNA/DNA, and that it can be compatible with a wide variety of backbone edifice. This provided the motivation to map the landscape of potentially primordial informational oligomer systems that may contain backbones, recognition elements and linker groups structurally quite different from those known so far. The oligomer systems chosen for study are, conceptually, deemed to be (a) potentially primordial (based on the nature of the starting materials and reaction conditions considered to be prebiotically realistic) and (b) informational (based on their ability to adopt a repetitive conformation such that the information encoded by the recognition elements can be transmitted intermolecularly). Though such studies suggest the possibility of finding informational systems that could lay claim as functional ancestors of RNA —they are more likely to generate results that provide the opportunity to assess the structural and functional uniqueness of nature’s choice. The experimental investigation described here deals with the base-pairing properties of oligomer systems derived from 2,4-disubsituted -triazines, -5-aminopyrimdines and -6-carboxy pyrimidines as recognition elements that are tagged to oligo-dipeptide backbones via different linker groups. The results from the inter- and intra-system cross-pairing studies reveal that there is, on first approximation, a direct correlation between the magnitude of the difference in DpKa of the recognition elements and their base-pairing strength —smaller the Dpka between the base-pairing partners, weaker is the base-pairing strength (in aqueous medium at near neutral pH). These results exemplify the inherent singularity of the canonical nucleobases— their ability to remain un-ionized under physiological conditions based on their constitution – emphasizing the relationship between their physicochemical properties and their functional competence in connection with their role in informational base-pairing.