Most proteins exert their biological effect by adopting a specific folded conformation, which is specified, in turn, by the sequence of amino acid side chains. Prior work has shown that a variety of unnatural peptidic backbones can mimic secondary structures found in natural proteins (helix, turn, sheet); however, more complex tertiary folds have proved elusive. Here we show methods to convert a natural protein with a defined teriary fold to an unnatural-backbone analogue with similar folding behavior. The underlying rationale of our work is that proteins have two sequences: (1) the canonical sequence of side chains and (2) an orthogonal sequence of backbone elements. In natural proteins, (2) is invariant and made up exclusively of alpha-amino acid residues. We are working to develop strategies for the systematic modification of natural backbones with diverse unnatural building blocks, many of which retain natural side-chain information. If such modifications are made judiciously, they can lead to unnatural backbones with the same tertiary fold as a parent protein sequence.

Sequence-guided backbone alteration for the mimicry of protein tertiary folding

246th National Meeting (2013)

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