Know your limit! IsoGNA (a structural isomer of GNA) was found—in sharp contrast to GNA—to be highly restricted in its ability to base-pair with itself and other nucleic acids. While homogeneous sequences (e.g. isoGNA(A)16) formed duplexes, the heterogeneous sequences showed no base-pairing. This exemplifies the limitations of canonical nucleobases as the recognition elements in simpler, more primitive phosphate backbones.