RNA folding is driven by the formation of double-helical segments interspaced by loops of unpaired nucleotides. Among the latter, bulges formed by one or several unpaired nucleotides are one of the most common structural motifs that play an important role in stabilizing RNA–RNA, RNA–protein, and RNA–small molecule interactions. Single-nucleotide bulges can fold in alternative structures where the unpaired nucleobase is either looped-out (flexible) in a solvent or stacked-in (intercalated) between the base pairs. In the present study, we discovered that triplex-forming peptide nucleic acids (PNAs) had unusually high affinity for single-purine-nucleotide bulges in double-helical RNA. Depending on the PNA’s sequence, the triplex formation shifted the equilibrium between looped-out and stacked-in conformations. The ability to control the dynamic equilibria of RNA’s structure will be an important tool for studying structure–function relationships in RNA biology and may have potential in novel therapeutic approaches targeting disease-related RNAs.

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