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Conformational control in peptoids, N-substituted glycines, is crucial for the design and synthesis of biologically-active compounds and atomically-defined nanomaterials. While there are a growing number of structural studies in solution, most have been performed with conformationally-constrained short sequences (e.g., sterically-hindered sidechains or macrocyclization). Thus, the inherent degree of heterogeneity of unconstrained peptoids in solution remains largely unstudied. Here, we explored the folding landscape of a series of simple peptoid tetramers in aqueous solution by NMR spectroscopy. By incorporating specific 13 C-probes into the backbone using bromoacetic acid-2- 13 C as a submonomer, we developed a new technique for sequential backbone assignment of peptoids based on the 1,n-Adequate pulse sequence. Unexpectedly, two of the tetramers, containing an N-(2-aminoethyl)glycine residue (Nae), had preferred conformations. NMR and molecular dynamics studies on one of the tetramers showed that the preferred conformer (52%) had a trans-cis-trans configuration about the three amide bonds. Moreover, >80% of the ensemble contained a cis amide bond at the central amide. The backbone dihedral angles observed fall directly within the expected minima in the peptoid Ramachandran plot. Analysis of this compound against similar peptoid analogs suggests that the commonly used Nae monomer plays a key role in the stabilization of peptoid structure via a side-chain-to-main-chain interaction. This discovery may offer a simple, synthetically high-yielding approach to control peptoid structure, and suggests that peptoids have strong intrinsic conformational preferences in solution. These findings should facilitate the predictive design of folded peptoid structures, and accelerate application in areas ranging from drug discovery to biomimetic nanoscience., (© 2019 Wiley Periodicals, Inc.)

Like polypeptides, peptoids, or N-substituted glycine oligomers, have intrinsic conformational preferences due to their amide backbones and close spacing of side chain substituents. However, the conformations that peptoids adopt are distinct from polypeptides due to several structural differences: the peptoid backbone is composed of tertiary amide bonds that have trans and cis conformers similar in energy, they lack a backbone hydrogen bond donor, and have an N-substituent. To better understand how these differences manifest in actual peptoid structures, we analyzed 46 high quality, experimentally determined peptoid structures reported in the literature to extract their backbone conformational preferences. One hundred thirty-two monomer dihedral angle pairs were compared to the calculated energy landscape for the peptoid Ramachandran plot, and were found to fall within the expected minima. Interestingly, only two regions of the backbone dihedral angles ϕ and ψ were found to be populated that are mirror images of each other. Furthermore, these two conformers are present in both cis and trans forms. Thus, there are four primary conformers that are sufficient to describe almost all known backbone conformations for peptoid oligomers, despite conformational constraints imposed by a variety of side chains, macrocyclization, or crystal packing forces. Because these conformers are predominant in peptoid structure, and are distinct from those found in protein secondary structures, we propose a simple naming system to aid in the description and classification of peptoid structure., (© 2019 Wiley Periodicals, Inc.)

Peptoids are positional isomers of peptides: peptoid sidechains are attached to backbone nitrogens rather than α-carbons. Peptoids constitute a class of sequence-specific polymers resistant to biological degradation and potentially as diverse, structurally and functionally, as proteins. While molecular simulation of proteins is commonplace, relatively few tools are available for peptoid simulation. Here, we present a first-generation atomistic forcefield for peptoids. Our forcefield is based on the peptide forcefield CHARMM22, with key parameters tuned to match both experimental data and quantum mechanical calculations for two model peptoids (dimethylacetamide and a sarcosine dipeptoid). We used this forcefield to demonstrate that solvation of a dipeptoid substantially modifies the conformations it can access. We also simulated a crystal structure of a peptoid homotrimer, H-(N-2-phenylethyl glycine)3 -OH, and we show that experimentally observed structural and dynamical features of the crystal are accurately described by our forcefield. The forcefield presented here provides a starting point for future development of peptoid-specific simulation methods within CHARMM., (Copyright © 2013 Wiley Periodicals, Inc.)

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 principles.