Researchers have demonstrated that a protein in which 20% of the building blocks are unnatural, such as β- or d-amino acids, can fold in a nativelike manner (J. Am. Chem. Soc. 2013, DOI: 10.1021/ja405422v). The work could lead to proteinlike therapeutics that last longer in the body because they are unnatural enough to evade recognition by protein-degrading enzymes. Proteinlike synthetic oligomers have been designed to adopt α-helix or β-sheet shapes and more complex forms such as helix bundles and helix-turn-helix motifs. But a general strategy for creating proteinlike unnatural oligomers that fold into complex three-dimensional conformations typical of natural proteins has been tough to pin down. Toward such a strategy, W. Seth Horne of the University of Pittsburgh and coworkers made several systematic backbone modifications in a bacterial protein that they predicted would not adversely affect the secondary structures in which the changes were located. They then combined the backbone changes with side-chain modifications to create an oligomer with a 20% unnatural backbone and showed that its folding behavior closely resembles the parent protein’s. The researchers believe that the complexity of the structure they mimicked and the variety of unnatural building blocks they used push the envelope of unnatural protein design.