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Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding.

ABSTRACT: The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent interactions that direct local peptoid folding. We have found that simple, peptoid monomer model systems allow for the effective isolation of individual interactions within the peptoid backbone and side chains and can facilitate the study of the role of these interactions in restricting local peptoid conformation. Herein, we present an analysis of a set of peptoid monomers and an oligomer containing N-aryl side chains capable of hydrogen bonding with the peptoid backbone. These model peptoids were found to exhibit well-defined local conformational preferences, allowing for control of the ?, ?, and ? dihedral angles adopted by the systems. Fundamental studies of the peptoid monomers enabled the design and synthesis of an acyclic peptoid reverse-turn structure, in which N-aryl side chains outfitted with ortho-hydrogen bond donors were hypothesized to play a critical role in the stabilization of the turn. This trimeric peptoid was characterized by X-ray crystallography and 2D NMR spectroscopy and was shown to adopt a unique acyclic peptoid reverse-turn conformation. Further analysis of this turn revealed an n??*(C?O) interaction within the peptoid backbone, which represents the first reported example of this type of stereoelectronic interaction occurring exclusively within a polypeptoid backbone. The installation of N-aryl side chains capable of hydrogen bonding into peptoids is straightforward and entirely compatible with current solid-phase peptoid synthesis methodologies. As such, we anticipate that the strategic incorporation of these N-aryl side chains should facilitate the construction of peptoids capable of adopting discrete structural motifs, both turnlike and beyond, and will facilitate the continued development of well-folded peptoids.

SUBMITTER: Stringer JR

PROVIDER: S-EPMC3175427 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding.

Stringer Joseph R JR Crapster J Aaron JA Guzei Ilia A IA Blackwell Helen E HE

The Journal of organic chemistry 20100901 18

The ability to design foldamers that mimic the defined structural motifs of natural biopolymers is critical for the continued development of functional biomimetic molecules. Peptoids, or oligomers of N-substituted glycine, represent a versatile class of foldamers capable of folding into defined secondary and tertiary structures. However, the rational design of discretely folded polypeptoids remains a challenging task, due in part to an incomplete understanding of the covalent and noncovalent int ...[more]

PMID: 20722367

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Project description:N-substituted glycine oligomers, or peptoids, have emerged as an important class of foldamers for the study of biomolecular interactions and for potential use as therapeutic agents. However, the design of peptoids with well-defined conformations a priori remains a formidable challenge. New approaches are required to address this problem, and the systematic study of the role of individual monomer units in the global peptoid folding process represents one strategy. Here, we report our efforts toward this approach through the design, synthesis, and characterization of peptoids containing nitroaromatic monomer units. This work required the synthesis of a new chiral amine building block, (S)-1-(2-nitrophenyl)ethanamine (s2ne), which could be readily installed into peptoids using standard solid-phase peptoid synthesis techniques. We designed a series of peptoid nonamers that allowed us to probe the effects of this relatively electron-deficient and sterically encumbered alpha-chiral side chain on peptoid structure, namely, the peptoid threaded loop and helix. Circular dichroism spectroscopy of the peptoids revealed that the nitroaromatic monomer has a significant effect on peptoid secondary structure. Specifically, the threaded loop structure was disrupted in a nonamer containing alternating N-(S)-1-phenylethylglycine (Nspe) and Ns2ne monomers, and the major conformation was helical instead. Indeed, placement of a single Ns2ne at the N-terminal position of (Nspe)(9) resulted in a destabilized form of the threaded loop structure relative to the homononamer (Nspe)(9). Conversely, we observed that incorporation of N-(S)-1-(4-nitrophenyl)ethylglycine (Nsnp, a p-nitro monomer) at the N-terminal position stabilized the threaded loop structure relative to (Nspe)(9). Additional experiments revealed that nitroaromatic side chains can influence peptoid nonamer folding by modulating the strength of key intramolecular hydrogen bonds in the peptoid threaded loop structure. Steric interactions were also implicated for the Ns2ne monomer. Overall, this study provides further evidence that aromatic side-chain structure, even if perturbed in a single monomer unit, can strongly influence local peptoid backbone conformation.

Dataset Information

Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding.

Publications

Construction of peptoids with all trans-amide backbones and peptoid reverse turns via the tactical incorporation of N-aryl side chains capable of hydrogen bonding.

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