The secondary structures of nucleic acids have an important influence on their cellular functions but can be difficult to identify and classify quickly. Here, we show that an arrayed suite of synthetic hosts and dyes is capable of fluorescence detection of oligonucleotide secondary structures. Multivariate analysis of different fluorescence enhancements—generated using cationic dyes that show affinity for both DNA G-quadruplexes and the synthetic hosts—enables discrimination between G-quadruplex structures of identical length and highly similar topological types. Different G-quadruplexes that display the same folding topology can also be easily differentiated by the number of G-quartets and sequence differences at the 3′ or 5′ ends. The array is capable of both differentiation and classification of the G-quadruplex structures at the same time. This simple non-invasive sensing method does not require the discovery and synthesis of specific G-quadruplex binding ligands, but employs a simple multicomponent approach to ensure wide applicability.
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