Exploring weak interactions realm with cyclic peptoids

A variety of non-covalent interactions, such as hydrophobic effect, hydrogen bonding, Coulombic contacts, and van der Waals interactions, influence the proper protein folding. Many investigations have shown that these conventional forces cannot be the only ones influencing protein folding, implying the involvement of weaker interactions. Thus, a plethora of "non-conventional" forces such as nπ* interactions, C5 hydrogen bonds, and C–H⸱⸱⸱O hydrogen bonds have emerged as co-protagonists to overall protein stabilization. Cyclic peptoids have recently been reported to be a simple and useful tool for the understanding of the aforementioned non-conventional interactions. These N-substituted oligomeric glycines are peptidomimetic compounds that stand out due to their unique properties. Aside from the possible applications, their solid state assembly has been extensively studied in recent years, revealing their ability to organize in a range of supramolecular structures. The crystal structures of four cyclic dodecapeptoids, decorated with a different combination of propargyl and methoxyethyl side-chains, revealed an unprecedented cccctcccct (c = cis, t = trans) amide bond configuration, defining two enantiomorphic right- and left-handed polyproline type I helices bridged by trans residues. It was demonstrated that this conformation is supported by the same type of non-conventional contacts that are essential for protein folding, establishing peptoids as an exceptional framework to explore the impact of weak interactions governing molecular self-organization.