Abstract
Synthetic polypeptides have received increasing attention due to their ability to form higher ordered structures similar to proteins. The control over their secondary structures, which enables dynamic conformational changes, is primarily accomplished by tuning the side-chain hydrophobic or ionic interactions. Herein we report a strategy to modulate the conformation of polypeptides utilizing donor-acceptor interactions emanating from side-chain H-bonding ligands. Specifically, 1,2,3-triazole groups, when incorporated onto polypeptide side-chains, serve as both H-bond donors and acceptors at neutral pH and disrupt the α-helical conformation. When protonated, the resulting 1,2,3-triazolium ions lose the ability to act as H-bond acceptors, and the polypeptides regain their α-helical structure. The conformational change of triazole polypeptides in response to the donor-acceptor pattern was conclusively demonstrated using both experimental-based and simulation-based methods. We further showed the utility of this transition by designing smart, cell-penetrating polymers that undergo acid-activated endosomal escape in living cells.Hydrogen bonding plays a major role in determining the tridimensional structure of biopolymers. Here, the authors show that control over a polypeptide conformation can be achieved by altering the donor-acceptor properties of side-chain triazole units via protonation-deprotonation.