NMR determination of the major solution conformation of a peptoid pentamer with chiral side chains

Abstract

Polymers of N-substituted glycines (''peptoids'') containing chiral centers at the ␣ position of their side chains can form stable structures in solution. We studied a prototypical peptoid, consisting of five para-substituted (S)-N-(1-phenylethyl)glycine residues, by NMR spectroscopy. Multiple configurational isomers were observed, but because of extensive signal overlap, only the major isomer containing all cis-amide bonds was examined in detail. The NMR data for this molecule, in conjunction with previous CD spectroscopic results, indicate that the major species in methanol is a right-handed helix with cis-amide bonds. The periodicity of the helix is three residues per turn, with a pitch of Ϸ6 Å. This conformation is similar to that anticipated by computational studies of a chiral peptoid octamer. The helical repeat orients the amide bond chromophores in a manner consistent with the intensity of the CD signal exhibited by this molecule. Many other chiral polypeptoids have similar CD spectra, suggesting that a whole family of peptoids containing chiral side chains is capable of adopting this secondary structure motif. Taken together, our experimental and theoretical studies of the structural properties of chiral peptoids lay the groundwork for the rational design of more complex polypeptoid molecules, with a variety of applications, ranging from nanostructures to nonviral gene delivery systems.Polymers of N-substituted glycines, termed peptoids, form a new class of biocompatible, synthetically accessible heteropolymers. Their sequence-specific, automated, and highly efficient synthesis has allowed the creation of combinatorial libraries of peptoid oligomers for drug discovery (1-3). By using recent improvements in the efficiency of the coupling chemistry, peptoids up to 50 residues in length have been synthesized. Among those, cationic peptoid 36-mers have been identified that bind DNA, protect the DNA from nuclease digestion, and facilitate gene transfection (4).We recently showed that many peptoids with chiral centers at the side chain ␣ position have strong CD signals, indicating the presence of a regularly repeating conformation, in both aqueous and organic solvents (5). This structure is remarkably stable, as demonstrated by both CD and differential scanning calorimetry (DSC) measurements (5). A model of this conformation was recently proposed based on the results of molecular mechanics and semi-empirical quantum mechanical calculations (6). Modeling predicted that peptoids containing (S)-N-(1-phenylethyl)glycine residues would form righthanded helices with a periodicity of approximately three residues per turn and cis-amide bonds, similar to the polyproline type I conformation. In this conformation, the backbone carbonyls are aligned along the long helical axis, providing an explanation for the intensity of the helical CD signal.Presented here is the structure determination by NMR spectroscopy of the major solution isomer of compound 1, a pentapeptoid containing five chiral side chains (Fig. 1A). ...

Surface-immobilised antimicrobial peptoids

“…PMP1-AMP and AMP exhibited similar spectral features, indicating the presence of a defined helical structure as was shown previously for AMP (Chongsiriwatana et al, 2008). The helical structures of PMP1-AMP and AMP are due to the incorporation of bulky α-chiral side chains which cause steric constraints (Armand et al, 1998;Wu et al, 2001;Sanborn et al, 2002;Wu et al, 2003). Peptoid C, PMP1-C and PMP1 10 did not have helical structures.…”

Impact of Helical Chain Shape in Sequence-Defined Polymers on Polypeptoid Block Copolymer Self-Assembly

“…30,31 By incorporating chiral side chains, polypeptoids can be induced to form a helical secondary structure 32−35 while polypeptoids with randomly incorporated, racemic side chains remain unstructured. 36 Helical conformations have been confirmed via a combination of circular dichroism, 32,37 2-D NMR, 33 and crystallography. 38,39 Further, we incorporate the polypeptoid helix at specific locations along the chain backbonespecifically examining the role of chain stretching at the edges of microdomains versus chain packing in the core of microdomains.…”

Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides

“…angles from a published NMR structure of a peptoid helix. (37,41) Because NLys is achiral, the structure of 1 is expected to be significantly dynamic in solution. Residues are color coded: cationic, blue; hydrophobic, orange; all others, gray.…”