The design of unnatural molecules with the intricate structural and functional features of proteins poses an important challenge for chemists. This task is particularly formidable when the target for mimicry manifests a complex tertiary folding pattern. This talk will describe some recent work from our lab on strategies for protein mimicry based on engineering the backbone of natural sequences. Blending natural α-amino acid residues with diverse unnatural building blocks (e.g., D-α-residues, β-residues, γ-residues) creates heterogeneous backbone oligomers that can show protein-like folding when they display native side-chain sequences. Topics covered will include: (1) design principles for modifying sheet, helix, turn, and loop secondary structures in a tertiary fold context; (2) the relationship between backbone connectivity and its susceptibility to proteolytic enzymes; and (3) changes to thermodynamics of folding that result from altered backbone structure.

Mimicry of protein tertiary structures by expanding beyond natural constraints of covalent connectivity in biological sequences

249th National Meeting (2015)

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