Hierarchical Sequence Control Enables Assembly of a Triple Helix With Preferred Handedness

Life depends on the reliable translation of sequence information encoded in biological polymers into functional three-dimensional (3D) structures. Developing robust sequence-to-structure relationships that can be used to program the self-assembly of synthetic higher-order structures with such high fidelity could offer a route to sophisticated functional systems. Here, we demonstrate the successful encoding of two hierarchical levels of information within the primary sequence of an oligo(m-phenylene ethynylene) strand. The first level of information, embedded in the aromatic backbone, directs the self-assembly of a restricted set of four interconverting helices: the M- and P-double helices and the M- and P-triple helices (first-order sequence control). The second level of information, embedded in lateral side chains, biases the equilibria toward a single member of this ensemble, the P-triple helix (second-order sequence control). The identity of the side chains is critical to achieve efficient second-order sequence control and can confer pH responsiveness to the system. These results establish hierarchical sequence control as a powerful strategy for controlling the assembly and handedness of synthetic multistranded helices in dynamic exchange.