Essential Contributions of Ribose and Nucleobases to the Nucleophilic Reactivity of RNA 2′‐OH Groups

ABSTRACT

The nucleophilic reactivity of sidechains of biopolymers is broadly enabling for bioscience and biomedicine, providing selective means for modifying them and analyzing their structures, interactions, and biological roles. Recent studies of RNA have shown that the 2′‐OH group is unusually reactive as a nucleophile to acyl and aryl electrophiles, reacting in water at rates far higher than simple alcohols, but the origins of this high reactivity are not well understood. Here we investigate the chemical origins of this nucleophilicity at the basic monomer level, measuring reaction kinetics of a broadly varied set of nucleosides, nucleotides, and sugars with four distinct electrophiles documented to react with RNA. We find that the nucleobases play unexpectedly influential roles in enhancing reactivity, by their presence, their size, and possibly their dipoles. We also find that the 2′‐OH of ribose (pentose) framework is unusually reactive as compared with that in structurally related hexose sugars. The results demonstrate that specific ribonucleoside structure contributes essentially to this nucleophilic reactivity, and likely influences RNA biology as a result.