Macrocycle folds up like a protein

Biological macromolecules such as proteins and nucleic acids can fold into complex shapes with well-defined architectures. A team led by Sijbren Otto of the University of Groningen, in collaboration with Ennio Zangrando of the University of Trieste and Piotr J. Chmielewski of the University of Wrocław, has now identified a small molecule that folds in a similar way to a protein, spontaneously assembling into a macrocycle called a foldamer (J. Am. Chem. Soc. 2018, DOI: 10.1021/jacs.8b11698). The building block consists of a nucleobase attached to an amino acid. At a concentration of ~500 µM, it assembles into a 15-subunit macrocycle that folds into a compact structure held in place by hydrogen bonds and π-stacking interactions. It has a highly twisted conformation, including five stacks of three aromatic rings, each stack capped with adenine rings. The spontaneous transition from small molecule to folded macromolecule is unusual, says Samuel H. Gellman, an expert on foldamers at the University of Wisconsin–Madison. “The discovery itself will stimulate others to consider new ways to explore the mystery of biomacromolecule development.”