pH-Controlled Reversible Folding of Copolymers via Formation of -sheet Secondary Structures

Protein functions are enabled by their perfectly arranged 3D structure, which is the result of a hierarchical intramolecular folding process. Sequence-defined polypeptide chains form locally ordered secondary structures (i.e., alpha-helix and beta-sheet) through hydrogen bonding between the backbone amides, shaping the overall tertiary structure. To generate similarly complex macromolecular architectures based on synthetic materials, a plethora of strategies have been developed to induce and control the folding of synthetic polymers. However, the degree of complexity of the structure-driving ensemble of interactions demonstrated by natural polymers is unreached, as synthesizing long sequence-defined polymers with functional backbones remains a challenge. Herein, we report the synthesis of hybrid peptide-N,N-Dimethylacrylamide copolymers via radical Ring-Opening Polymerization (rROP) of peptide containing macrocycles. The resulting synthetic polymers contain sequence-defined regions of beta-sheet encoding amino acid sequences. Exploiting the pH responsiveness of the embedded sequences, protonation or deprotonation in water induces self-assembly of the peptide strands at an intramacromolecular level, driving polymer chain folding via formation of beta-sheet secondary structures. We demonstrate that the folding behavior is sequence dependent and reversible. Using radical ring-opening polymerization, short pH-responsive peptides are embedded into the main chain of vinylic polymers. Controlled by pH, these defined peptide sequences dictate the reversible folding of their parent polymers into hydrogen-bonded architectures, effectively mirroring the translation from primary to higher-order structures.image