Orthogonal DNA barcodes enable the high-throughput screening of sequence-defined polymers

Polymers with sequence definition allow access to programmable morphologies and applications, but directly correlating polymer structure to function currently requires case-by-case analysis: high throughput methods that identify promising species from entire chemical families are required. Here, we show that the discovery of effective protein target-recognition molecules can be achieved using DNA-encoded libraries of chemically diverse sequence-defined oligomers, generated on an automated DNA synthesizer. These structures are ALENOMERs – Aptamer-Like ENcoded OligoMERs – that are read and sequenced using a DNA code that branches from, and corresponds to, the target-binding oligomer. By incorporating nucleosidic and non-nucleosidic components into alenomers at specific locations, we unlock new supramolecular interactions for biomolecule binding, and directly correlate their effectiveness at each site. Our alenomer library screening removes the low throughput bottleneck of analyzing individual sequence-defined polymers, improving the binding efficacies of natural systems and enabling wide chemical spaces to be sampled for biomolecule sensing, therapy, and diagnostics.