A team led by Prof. Huaimin Wang at Westlake School of Science has designed an alternative strategy to design reversible higher-order assemblies of the asymmetrical cyclic peptides to recreate and validate the naturally occurring chirality inversion prior to cyclization in water.

Chirality correction, asymmetry, ring-chain tautomerism and hierarchical assemblies are fundamental phenomena in nature. They are geometrically related and may impact the biological roles of a protein or other supermolecules. Studying those behaviors, however, is difficult due to the complexity of displaying these features within an artificial system.

The innovative strategy developed by the Westlake researchers could help tackle these challenges.

Their design of a cyclic peptide platform with a reversible linkage demonstrates that a rationally designed peptide could mimic multiple natural phenomena and promote the development of functional biomaterials, catalysts, antibiotics, and supermolecules.

Their new findings have been published in the journal Angew. Chem., under the title “Dynamic Control of Cyclic Peptide Assembly to Form Higher Order Assemblies.”  

(Figure 1. Schematic illustration of the irreversible and reversible cyclization and the assembly of the cyclic monomers. a) Irreversible cyclization of the linear peptide through an amide bond formation, and the assembly of cyclic monomers to form 1D nanotubes and 2D nanosheets. b) Thermal-induced reversible cyclization of a cyclic D,L peptide with an asymmetrical backbone and the spontaneous assembly to form intertwined hierarchical nanostructures in water. Neutral or slightly basic conditions favor for the cyclization, while acidic conditions induce ring-opening.)

Supramolecular nanotubular structures formed by proteins are prevalent within biological membranes, which can facilitate intercellular communication and pathologies detection. To fulfill the various biological functions, the dynamic high-order assemblies (e.g., tertiary structures) of proteins are the prerequisite requirement.

For the study, the researchers designed an alternating D,L peptide to recreate and validate the naturally occurring chirality inversion prior to cyclization in water. The resulted asymmetrical cyclic peptide containing a 4-imidazolidinone ring provided an excellent platform to study the ring-chain tautomerism, thermostability and dynamic assembly of the nanostructures.

Overall, this work shows that the asymmetrical incorporation of a hetero ring in the backbone of cyclic D,L peptides could promote the formation of intertwined hierarchical nanostructures rather than classical nanotubes or nanosheets.

According to the researchers, different from traditional cyclic D,L peptides, the formation of 4-imidazolidinone promotes the formation of intertwined nanostructures, and may guide the development of new cyclic peptides and nanomaterials with various structural and functional features.

The study was supported by the National Key Research Development and the National Natural Science Foundation of China.