Manipulating the helix–coil transition profile of synthetic polypeptides by leveraging side-chain molecular interactions

Polypeptides with trigger-responsive helix–coil transition behaviours are interesting biomaterials due to their helix-specific assemblies and biomedical performances. Based on the pH-sensitive, conformationally switchable triazole polypeptides, we reported the manipulation of the helix–coil transition profile, which was determined by the combined molecular interactions of triazole and other side-chain functionalities. Specifically, the introduction of side-chain hydrophobic moieties or hydrogen bonding acceptors neutralized the helix-disrupting effect of side-chain triazoles, which altered the pH-responsive conformational transition profile of the polypeptides. These results inspired us to design new triazole polypeptides bearing dimethylamino side chains, which exhibited interesting helix–coil–helix transition behaviours as the pH decreased.