Self-assembly properties and diversity
in higher-order structures
of DNA enable programmable tools to be used to construct algorithms
at the molecular level. However, the utility of DNA-based programmable
tools is hampered by the low orthogonality to natural nucleic acids,
especially in complex molecular systems. To address this challenge,
we report here the orthogonal regulation of DNA self-assembly by using
an unnatural base pair (UBP) formation. Our newly designed UBP AnN:SyN is formed in combination with anti and unusual syn glycosidic conformation with high thermal stability
and selectivity. Furthermore, AnC worked as a pH-sensitive artificial nucleobase, which forms a strong
base pair with cytosine under a weak acidic condition (pH 6.0). The
orthogonal AnN:SyN base pair functioned as a trigger for hybridization
chain reaction to provide long nicked double-stranded DNA (ca. 1000
base pairs). This work represents the first example of the orthogonal
DNA self-assembly that is nonreactive to natural four-letter alphabets
DNA trigger and expands the types of programmable tools that work
in a complex environment.