Was a Pyrimidine‐Pyrimidine Base Pair the Ancestor of Watson‐Crick Base Pairs? Insights from a Systematic Approach to the Origin of RNA

Abstract

AbstractUncovering the origin of RNA is essential for understanding the origins of life. The persistent inability of chemists to identify a plausible prebiotic route to RNA polymers, along with the seemingly optimal structure of RNA for its functions in extant life, argue in favor of the hypothesis that RNA is a product of chemical or biological evolution. To understand the origin of RNA, we must consider which molecules could have originally acted in place of RNA’s substructures (i.e., nucleobases (the recognition units), ribose (a trifunctional connector), and phosphate (an ionized linker)) in the oldest ancestor of RNA (or proto‐RNA). Major challenges to uncovering the chemical structure of proto‐RNA include finding molecules that would have spontaneously undergone molecular selection and covalent assembly into an RNA‐like polymer, within the complex mixture of the “prebiotic soup” and without the aid of enzymes. In this review, we discuss progress towards identifying the recognition units of proto‐RNA and mechanisms by which the ancestral nucleobases might have been originally selected and incorporated into polymers. We consider possible proto‐nucleobases within the chemical space of the heterocycles defined by the purines and pyrimidines that have H, NH2, or O as exocyclic groups (which includes the extant nucleobases). Taking into account the results of numerous experiments that have explored nucleic acids with alternative backbones and noncanonical nucleobases, we are able to remove about half of these 81 molecules from candidacy as ancestral nucleobases. A particularly encouraging result of this approach is the identification of two molecules, 2,4,6‐triaminopyrimidine and barbituric acid, which look very promising as possible nucleobases of proto‐RNA.