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Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.

ABSTRACT: 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.

SUBMITTER: George KL

PROVIDER: S-EPMC5512705 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.

George Kelly L KL Horne W Seth WS

Journal of the American Chemical Society 20170605 23

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 na ...[more]

PMID: 28509549

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Project description:The prospect of recreating the complex structural hierarchy of protein folding in synthetic oligomers with backbones that are artificial in covalent structure ("foldamers") has long fascinated chemists. Foldamers offer complex functions from biostable scaffolds and have found widespread applications in fields from biomedical to materials science. Most precedent has focused on isolated secondary structures or their assemblies. In considering the goal of complex protein-like tertiary folding patterns, a key barrier became apparent. How does one design a backbone with covalent connectivity and a sequence of side-chain functional groups that will support defined intramolecular packing of multiple artificial secondary structures? Two developments were key to overcoming this challenge. First was the recognition of the power of blending ?-amino acid residues with monomers differing in backbone connectivity to create "heterogeneous-backbone" foldamers. Second was the finding that replacing some of the natural ?-residues in a biological sequence with artificial-backbone variants can result in a mimic that retains both the fold and function of the native sequence and, in some cases, gains advantageous characteristics. Taken together, these precedents lead to a view of a protein as chemical entity having two orthogonal sequences: a sequence of side-chain functional groups and a separate sequence of backbone units displaying those functional groups. In this Account, we describe our lab's work over the last ?10 years to leverage the above concept of protein sequence duality in order to develop design principles for constructing heterogeneous-backbone foldamers that adopt complex protein-like tertiary folds. Fundamental to the approach is the utilization of a variety of artificial building blocks (e.g., d-?-residues, C?-Me-?-residues, N-Me-?-residues, ?-residues, ?-residues, ?-residues, polymer segments) in concert, replacing a fraction of ?-residues in a given prototype sequence. We provide an overview of the state-of-the-art in terms of design principles for choosing substitutions based on consideration of local secondary structure and retention of key side-chain functional groups. We survey high-resolution structures of backbone-modified proteins to illustrate how diverse artificial moieties are accommodated in tertiary fold contexts. We detail efforts to elucidate how backbone alteration impacts folding thermodynamics and describe how such data informs the development of improved design rules. Collectively, a growing body of results by our lab and others spanning multiple protein systems suggests there is a great deal of plasticity with respect to the backbone chemical structures upon which sequence-encoded tertiary folds can manifest. Moreover, these efforts suggest sequence-guided backbone alteration as a broadly applicable strategy for generating foldamers with complex tertiary folding patterns. We conclude by offering some perspective regarding the near future of this field, in terms of unanswered questions, technological needs, and opportunities for new areas of inquiry.

Dataset Information

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.

Publications

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure.

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