Covalent bonds between amino acid side chains help stabilize protein structures and interactions. The ability to form types of covalent bonds other than disulfide bonds between cysteines could make it possible to design proteins with a wider variety of properties and functions. Lei Wang and coworkers at the Salk Institute for Biological Studies, in La Jolla, Calif., use well-established methods to incorporate into proteins unnatural amino acids that form covalent bonds not normally seen in proteins (Nat. Methods 2013, DOI: 10.1038/nmeth.2595). Researchers have previously avoided unnatural amino acids that react with other side chains, opting instead for so-called bioorthogonal side chains. Wang and coworkers designed p-2´-fluoroacetylphenylalanine to react with cysteine (reaction shown). The reaction occurs only when the two amino acids are close to one another in the same protein or interacting proteins. The researchers show that when the unnatural amino acid is incorporated in an antibody mimetic, it enables irreversible binding between the mimetic and its protein substrate. They suspect the approach will also work with unnatural amino acids designed to react with amino acids other than cysteine.