In peptoid self-assembly, the most exciting development of the past year has been the synthesis of peptoid nanosheets, crystalline bilayers with a thickness of 2.7 nm and transverse dimensions that can exceed 100 microns.
In a fundamental physical sense, the enormous design space opened by modern foldamer technologies offers enormous potential, but to make effective use of that physical potential will require software tools to support what amounts to a new field of engineering. Biology-based evolutionary methods (such as SELEX and phage display) are unavailable in peptoid engineering, and this highlights the importance of developing design-based methods. Protein design provides a model that illustrates the nature of the problem and some of the solutions.
The key question for engineering, isn’t ‘‘What remains to be discovered?’’,
but rather, ‘‘What is visibly within reach?’’ The tool kit in hand for peptoid engineering is large and growing, and has already proved adequate for engineering protein-scale macromolecular objects. Exploiting side-chain diversity offers many ways to increase the predictability and stability of folds, many ways to link folded structures to form larger systems, and many ways to imbue those structures with new functions. This is enough to move forward, and with confidence that the path leads beyond today’s horizon.
Methods for engineering biomolecular systems based on DNA and protein are advancing rapidly, building a technology platform for engineering increasingly large and complex self-assembled nanosystems. A comparative review of the physical basis for DNA, protein, and peptoid engineering indicates that the characteristics of peptoids suit them for a strong role in developing self-assembled nanosystems. Physical parallels between peptoids and proteins indicate that peptoid engineering, like protein engineering, will require specialized software to support design. Access to novel side-chain functionality will enable peptoid designers to exploit novel binding interactions, including many that have been discovered and exploited in crystal engineering, a field that has extensively explored the self-assembly of small organic molecules to form well-ordered structures. Developments in DNA, protein, and inorganic nanotechnologies are converging to provide a technology platform for the design and fabrication of complex, functional, atomically precise nanosystems. Peptoid-based foldamer technologies can contribute to this convergence, expanding the scope of the emerging field of atomically precise macromolecular nanosystems
Folding of a single-chain, information-rich polypeptoid sequence into a highly ordered nanosheet
The design and synthesis of protein-like polymers is a fundamental challenge in materials science. A means to achieve this goal is to create synthetic polymers of defined sequence where all relevant folding information is incorporated into a single polymer strand. We present here the aqueous self-assembly of peptoid polymers (N-substituted glycines) into ultrathin, two-dimensional highly ordered nanosheets, where all folding information is encoded into a single chain. The sequence designs enforce a two-fold amphiphilic periodicity. Two sequences were considered: one with charged residues alternately positive and negative (alternating patterning), and one with charges segregated in positive and negative halves of the molecule (block patterning). Sheets form between pH 5 and 10 with the optimal conditions being pH 6 for the alternating sequence and pH 8 for the block sequence. Once assembled, the nanosheets remain stable between pH 6 and 10 with observed degradation beginning to occur below pH 6. The alternating charge nanosheets remain stable up to concentrations of 20% acetonitrile, whereas the block pattern displayed greater robustness remaining stable up to 30% acetonitrile. These observations are consistent with expectations based on considerations of the molecules' electrostatic interactions. This study represents an important step in the construction of abiotic materials founded on biological informatic and folding principle
Oligo(N-alkoxy glycines): Trans substantiating peptoid conformations
Peptoid oligomers possess many desirable attributes as bioactive peptidomimetic agents, including their ease of synthesis, chemical diversity, and capability for molecular recognition. Ongoing efforts to develop functional peptoids will necessitate improved capability for control of peptoid structure, particularly of the backbone amide conformation. We introduce alkoxyamines as a new reagent for solid phase peptoid synthesis. Herein, we describe the synthesis of N-alkoxy peptoids, and present NMR data indicating that the oligomers adopt a single stable conformation featuring trans amide bonds. These findings, combined with results from computational modeling, suggest that N-alkoxy peptoid oligomers have a strong propensity to adopt a polyproline II type secondary structure
We have demonstrated that chiral N-alkoxy peptoid oligomers can be prepared using standard peptoid submonomer synthesis protocols. The N-alkoxy amide units favor trans-amide bonds that exhibit a greater extent of ordering than corresponding N-alkyl peptoids. An accompanying study in this issue by the Blackwell group of N-hydroxy amide peptoids similarly confirms that the presence of the side chain oxygen atom can direct the formation of trans-amide conformers.33 Quantum mechanics calculations have recapitulated the experimental investigations, and we have thoroughly explored the backbone and side-chain torsional energetics. CD and one dimensional proton NMR experiments indicate that peptoids of longer oligomer lengths maintain the overall order of the dimer 2. Based upon these results, we have constructed a model of the secondary structure formed by an N-alkoxy peptoid oligomer consisting of (S)-O-(1-phenylethyl) side-chains. The resulting polyproline II type helix bears a resemblance to oligomeric N-aryl peptoids, which are also known to form stable trans-amide bonds. The N-alkoxy glycine monomer units represent a new strategy for design of peptoid oligomer structure and may provide a general means to control amide bond geometry.
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