Peptoids with Folded Structure

If peptide residues are converted to peptoid residues, the conformational heterogeneity of the polymer backbone is likely to increase due to cis/trans isomerization at amide bonds. This will lead to an enhanced loss of conformational entropy upon peptoid/protein association, which could adversely affect binding thermodynamics. A potential solution is the judicious placement of bulky peptoid side chains that constrain backbone dihedral angles. 

If the individual residues of a peptide are transformed into the corresponding peptoid monomers to make hybrid oligomers, there will be a perturbation in the distance between side chains at the boundary between oligomer types. That is, spacing of side chains at a peptoid-peptide linkage will be different from that between either two peptide or peptoid residues. 

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Proteins derive their powerful and diverse capacity for molecular recognition and catalysis from their ability to fold into defined secondary and tertiary structures and display specific functional groups at precise locations in space. Functional protein domains are typically 50-200 residues in length and utilize a specific sequence of side chains to encode folded structures that have a compact hydrophobic core and a hydrophilic surface. Mimicry of protein structure and function by non-natural ohgomers such as peptoids wiU not only require the synthesis of >50mers with a variety of side chains, but wiU also require these non-natural sequences to adopt, in water, tertiary structures that are rich in secondary structure. 

Patch, ).A., Wu, C.W., Sanborn, T.J., Huang, K., Zuckermann, R.N., Barron, A. E., and Radhakrishnan, I. A peptoid oligomer with a unique, cyclic folded structure and a solvent-depend conformational switch. (Manuscript in preparation). 

In order for folded helices to assemble into tertiary structures in water, they need to be amphipathic (e.g. where one hehcal face is hydrophobic and the other is hydrophilic). Because the first hehcal peptoids contained very hydrophobic chiral residues, ways to increase the water solubihty and side-chain diversity of the hehx-indudng residues were investigated [49]. It was found that a series of side chains with chiral-substituted carboxamides in place of the aromatic group could stiU favor hehx formation, while dramatically increasing water solubility. 

The only published X-ray diffraction structure for any peptoid oligomer, the Nrch (8) homo-pentamer, shows clearly that the molecule is folded in a left-handed helical conformation with... 

Gorske, B. C. and Blackwell, H. E. (2006) Tuning peptoid secondary structure with pentafluo-roaromatic functionality A new design paradigm for the construction of discretely folded peptoid structures. Journal of the American Chemical Society, 128(44), 14378-14387. 

Overall, research in peptoid-based secondary stmctures has made tremendous advances in the last few years. Researchers now understand the folding behavior even better and, recently, the first de novo structure prediction was presented [89]. Also, the first tentative studies towards application of peptoid secondary stmctures can be found in the literature. A peptoid heptamer that includes a side chain with TEMPO (2,2,6,6-tetramethylpiperidine-l-oxyl) showed a strong potential for enantioselective catalytic transformations. Importantly, the enantios-electivity was strongly dependent on the sequence of the peptoid [90]. In enzymes, the tertiary stmcture is important for their catalytic activity. Therefore, it is only natural that researchers are also attempting to mimic the tertiary stmcture of proteins with peptoids. In a few cases, these attempts have already proved fruitful. 

The subject of this section is the self-assembly of different peptoid (macro-) molecules, something which could be also termed the quaternary structure. We are aware that for structural biologists, quaternary structure is a more or less exactly defined supramolecular assembly of multiple folded proteins. We shall not be so strict, if only to leave room for creativity in what might be accomplished with peptoids in the future. In this section, we will discuss briefly supramolecular structures that have been reported using peptoids. Naturally, this is a field much closer to the heart of the polymer chemist. 

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