This work studies the effect of RNA structure on the reactivity of RNA phosphodiester bonds. The aim of the study is to evaluate those structural parameters that affect reactivity to support the development of sequence-specific RNA cleaving agents. The cleavage of phosphodiester bonds within one-to five-nucleotide bulges has been studied in buffer solutions (pH 8.4), and in the presence of Zn 2ϩ aqua ion (pH 6.4) or its 1,5,9-triazacyclododecane complex (pH 7.4). Molecular modelling has been applied to study the structure of the substrates. The basis of the reactivity and the catalytic potential of metal ion-based cleaving agents are discussed.