ConspectusNucleic acids represent a unique class of highly programmable molecules, where the sequence of monomer units incorporated into the polymer chain can be read through duplex formation with a complementary oligomer. It should be possible to encode information in synthetic oligomers as a sequence of different monomer units in the same way that the four different bases program information into DNA and RNA. In this Account, we describe our efforts to develop synthetic duplex-forming oligomers composed of sequences of two complementary recognition units that can base-pair in organic solvents through formation of a single H-bond, and we outline some general guidelines for the design of new sequence-selective recognition systems.The design strategy has focused on three interchangeable modules that control recognition, synthesis, and backbone geometry. For a single H-bond to be effective as a base-pairing interaction, very polar recognition units, such as phosphine oxide and phenol, are required. Reliable base-pairing in organic solvents requires a nonpolar backbone, so that the only polar functional groups present are the donor and acceptor sites on the two recognition units. This criterion limits the range of functional groups that can be produced in the synthesis of oligomers. In addition, the chemistry used for polymerization should be orthogonal to the recognition units. Several compatible high yielding coupling chemistries that are suitable for the synthesis of recognition-encoded polymers are explored. Finally, the conformational properties of the backbone module play an important role in determining the supramolecular assembly pathways that are accessible to mixed sequence oligomers.Almost all complementary homo-oligomers will form duplexes provided the product of the association constant for formation of a base-pair and the effective molarity for the intramolecular base-pairing interactions that zip up the duplex is significantly greater than one. For these systems, the structure of the backbone does not play a major role, and the effective molarities for duplex formation tend to fall in the range 10-100 mM for both rigid and flexible backbones. For mixed sequences, intramolecular H-bonding interactions lead to folding. The competition between folding and duplex formation depends critically on the conformational properties of the backbone, and high-fidelity sequence-selective duplex formation is only observed for backbones that are sufficiently rigid to prevent short-range folding between bases that are close in sequence. The final section of the Account highlights the prospects for functional properties, other than duplex formation, that might be encoded with sequence.Engineering and Physical Sciences Research Council (EP/P027067/1), the European Research Council (ERC-2012-AdG 320539-duplex and ERC-2020-AdG101018984- InfoMols) and the Herchel Smith Fund
