Due to the vital roles proteins play in life, much effort has been invested in their mimicry by synthetic agents. One approach to this goal is to design unnatural backbone oligomers (“foldamers”) that fold like natural peptides. Despite success in secondary structure mimicry by such species, protein-like tertiary folds remain elusive. A fundamental challenge underlying this task is the design of a sequence of side chains that will specify a complex tertiary folding pattern on an unnatural backbone. We report here a sequence-based approach to convert a natural protein with a compact tertiary fold to an analogue with a backbone composed of ∼20% unnatural building blocks but similar folding behavior as the parent protein.
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