Modifying elements of a peptide's backbone yields nonnatural peptides that reproduce the three-dimensional structure of the original amino acid sequence, a strategy that could help in designing protein mimics (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.0801135105). Researchers have long studied how the side chains of amino acids affect peptide folding, but little is understood about the influence of a peptide's backbone. To gain new insight on the backbone's role, Samuel H. Gellman and coworkers at the University of Wisconsin, Madison, substituted selected α-amino acid residues in a very stable four-helix protein with β-amino acid counterparts without changing the side-chain sequence. Despite the extra atoms introduced into the backbone with the β-residues, several substitution patterns closely approximated the original protein's helical structure, as determined by X-ray crystallography. The best replicas contained cyclic β-residues to make certain segments of the backbone more rigid. "Gellman and coworkers have taken another important step in the development of an expanded set of building blocks to engineer proteins," says William F. DeGrado, a protein design expert at the University of Pennsylvania.