Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

• Published in: Journal of the American Chemical Society Vol. 139; no. 23; pp. 7931 - 7938
• Main Authors: George, Kelly L, Horne, W. Seth
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 14.06.2017; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; ALPHA/BETA-PEPTIDES; DESIGN; PROTEIN; THERMODYNAMICS; METAL-BINDING; METALLOFOLDAMERS; HIGH-AFFINITY; GENE-REGULATION; COORDINATION; MODEL
• DOI: 10.1021/jacs.7b03114
• ISSN: 0002-7863

A variety of oligomeric backbones with compositions deviating from biomacromolecules can fold in defined ways. Termed “foldamers,” these agents have diverse potential applications. A number of protein-inspired secondary structures (e.g., helices, sheets) have been produced from unnatural backbones, yet examples of tertiary folds combining several secondary structural elements in a single entity are rare. One promising strategy to address this challenge is the systematic backbone alteration of natural protein sequences, through which a subset of the native side chains is displayed on an unnatural building block to generate a heterogeneous backbone. A drawback to this approach is that substitution at more than one or two sites often comes at a significant energetic cost to fold stability. Here we report heterogeneous-backbone foldamers that mimic the zinc finger domain, a ubiquitous and biologically important metal-binding tertiary motif, and do so with a folded stability that is superior to the natural protein on which their design is based. A combination of UV–vis spectroscopy, isothermal titration calorimetry, and multidimensional NMR reveals that suitably designed oligomers with >20% modified backbones can form native-like tertiary folds with metal-binding environments identical to the prototype sequence (the third finger of specificity factor 1) and enhanced thermodynamic stability. These results expand the scope of heterogeneous-backbone foldamer design to a new tertiary structure class and show that judiciously applied backbone modification can be accompanied by improvement to fold stability.