Understanding Sequence Contributions to Peptoid–lipid Interactions: Using Peptoids as a Platform to Advance Multidisciplinary Research and Undergraduate Education in Parallel (original) (raw)

2018

https://doi.org/10.26434/CHEMRXIV.7198559

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Abstract

The synthesis and fluorescence spectroscopy studies of 21 peptoids, including 19 new tripeptoids, are described. Insight into sequence features that influence biophysical properties in the presence and absence of unilamellar lipid vesicles is provided. Concomitantly, we highlight the educational value of training undergraduates in multidisciplinary research using peptoid science.

Structural and spectroscopic studies of peptoid oligomers with α-chiral aliphatic side chains

Journal of the …, 2003

Substantial progress has been made in the synthesis and characterization of various oligomeric molecules capable of autonomous folding to well-defined, repetitive secondary structures. It is now possible to investigate sequence-structure relationships and the driving forces for folding in these systems. Here, we present detailed analysis by X-ray crystallography, NMR, and circular dichroism (CD) of the helical structures formed by N-substituted glycine (or "peptoid") oligomers with R-chiral, aliphatic side chains. The X-ray crystal structure of a N-(1-cyclohexylethyl)glycine pentamer, the first reported for any peptoid, shows a helix with cis-amide bonds, ∼3 residues per turn, and a pitch of ∼6.7 Å. The backbone dihedral angles of this pentamer are similar to those of a polyproline type I peptide helix, in agreement with prior modeling predictions. This crystal structure likely represents the major solution conformers, since the CD spectra of analogous peptoid hexamers, dodecamers, and pentadecamers, composed entirely of either (S)-N-(1cyclohexylethyl)glycine or (S)-N-(sec-butyl)glycine monomers, also have features similar to those of the polyproline type I helix. Furthermore, this crystal structure is similar to a solution NMR structure previously described for a peptoid pentamer comprised of chiral, aromatic side chains, which suggests that peptoids containing either aromatic or aliphatic R-chiral side chains adopt fundamentally similar helical structures in solution, despite distinct CD spectra. The elucidation of detailed structural information for peptoid helices with R-chiral aliphatic side chains will facilitate the mimicry of biomolecules, such as transmembrane protein domains, in a distinctly stable form.

Structural and Spectroscopic Studies of Peptoid Oligomers with r-Chiral Aliphatic Side Chains

Structural and Dynamical Characteristics of Peptoid Oligomers with Achiral Aliphatic Side Chains Studied by Molecular Dynamics Simulation

The Journal of Physical Chemistry B, 2011

All-atom molecular dynamics simulations of N-substituted glycine peptoid oligomers with methyl and methoxyethyl side chains have been carried out for chain lengths of 5, 10, 20, and 50 residues in aqueous phase at room temperature. The (ϕ, ψ backbone dihedral angle distributions in the Ramachandran plots show that helical structures, similar to polyproline type I and type II helices, are the most favorable conformations in most peptoid oligomers studied. The left-handed helical structures are shown to be increasingly favored as the oligomer chain length grows. A significant population of cis amide bond configuration has been identified in the peptoid oligomers. By combining the analysis of ϕ and ω backbone dihedral angles, we determined the relative composition of the four major conformations favored by the backbone dihedral angles. The trans α D conformation is found to be most favored for all peptoid oligomers studies. The time correlation functions of the end-to-end distance highlight a rigid backbone structure relative to side chains for peptoid oligomers. The transition between right-handed and left-handed helical conformation is found to be very rare, and between cis and trans isomerism in amide bond completely absent in the simulation time scale. The radii of gyration for all peptoid oligomers have been found to be consistently larger in comparison to the peptide counterparts, suggesting slightly open structures for peptoids relative to peptides, while the fluctuations in the radius of gyration support a rigid backbone structure of peptoids.

De novo structure prediction and experimental characterization of folded peptoid oligomers

Peptoid molecules are biomimetic oligomers that can fold into unique three-dimensional structures. As part of an effort to advance computational design of folded oligomers, we present blind-structure predictions for three peptoid sequences using a combination of Replica Exchange Molecular Dynamics (REMD) simulation and Quantum Mechanical refinement. We correctly predicted the structure of a N-aryl peptoid trimer to within 0.2 Å rmsd-backbone and a cyclic peptoid nonamer to an accuracy of 1.0 Å rmsd-backbone. X-ray crystallographic structures are presented for a linear N-alkyl peptoid trimer and for the cyclic peptoid nonamer. The peptoid macrocycle structure features a combination of cis and trans backbone amides, significant nonplanarity of the amide bonds, and a unique “basket” arrangement of (S)-N(1-phenylethyl) side chains encompassing a bound ethanol molecule. REMD simulations of the peptoid trimers reveal that well folded peptoids can exhibit funnel-like conformational free energy landscapes similar to those for ordered polypeptides. These results indicate that physical modeling can successfully perform de novo structure prediction for small peptoid molecules.

Peptoid oligomers with α-chiral, aromatic side chains: sequence requirements for the formation of stable peptoid helices

Journal of the …, 2001

The achiral backbone of oligo-N-substituted glycines or "peptoids" lacks hydrogen-bond donors, effectively preventing formation of the regular, intrachain hydrogen bonds that stabilize peptide R-helical structures. Yet, when peptoids are N-substituted with R-chiral, aromatic side chains, oligomers with as few as five residues form stable, chiral, polyproline-like helices in either organic or aqueous solution. The adoption of chiral secondary structure in peptoid oligomers is primarily driven by the steric influence of these bulky, chiral side chains. Interestingly, peptoid helices of this class exhibit intense circular dichroism (CD) spectra that closely resemble those of peptide R-helices. Here, we have taken advantage of this distinctive spectroscopic signature to investigate sequence-related factors that favor and disfavor stable formation of peptoid helices of this class, through a comparison of more than 30 different heterooligomers with mixed chiral and achiral side chains. For this family of peptoids, we observe that a composition of at least 50% R-chiral, aromatic residues is necessary for the formation of stable helical structure in hexameric sequences. Moreover, both CD and 1 H-13 C HSQC NMR studies reveal that these short peptoid helices are stabilized by the placement of an R-chiral, aromatic residue on the carboxy terminus. Additional stabilization can be provided by the presence of an "aromatic face" on the helix, which can be patterned by positioning aromatic residues with three-fold periodicity in the sequence. Extending heterooligomer chain length beyond 12-15 residues minimizes the impact of the placement, but not the percentage, of R-chiral aromatic side chains on overall helical stability. In light of these new data, we discuss implications for the design of helical, biomimetic peptoids based on this structural motif.

Peptoid oligomers with α-chiral, aromatic side chains: effects of chain length on secondary structure

Journal of the …, 2001

Oligomeric N-substituted glycines or "peptoids" with R-chiral, aromatic side chains can adopt stable helices in organic or aqueous solution, despite their lack of backbone chirality and their inability to form intrachain hydrogen bonds. Helical ordering appears to be stabilized by avoidance of steric clash as well as by electrostatic repulsion between backbone carbonyls and π clouds of aromatic rings in the side chains. Interestingly, these peptoid helices exhibit intense circular dichroism (CD) spectra that closely resemble those of peptide R-helices. Here, we have utilized CD to systematically study the effects of oligomer length, concentration, and temperature on the chiral secondary structure of organosoluble peptoid homooligomers ranging from 3 to 20 (R)-N-(1-phenylethyl)glycine (Nrpe) monomers in length. We find that a striking evolution in CD spectral features occurs for Nrpe oligomers between 4 and 12 residues in length, which we attribute to a chain length-dependent population of alternate structured conformers having cis versus trans amide bonds. No significant changes are observed in CD spectra of oligomers between 13 and 20 monomers in length, suggesting a minimal chain length of about 13 residues for the formation of stable poly(Nrpe) helices. Moreover, no dependence of circular dichroism on concentration is observed for an Nrpe hexamer, providing evidence that these helices remain monomeric in solution. In light of these new data, we discuss chain length-related factors that stabilize organosoluble peptoid helices of this class, which are important for the design of helical, biomimetic peptoids sharing this structural motif. Figure 3. A side-by-side comparison of the three different classes of CD signatures that are obtained for Nrpe peptoid oligomers between 3 and 20 monomers in length. Spectra of oligomers (a) 6, (b) 9, and (c) 20 are compared. Data were acquired at room temperature and the sample concentration was ∼60 µM.

Incorporation of heterocycles into the backbone of peptoids to generate diverse peptoid-inspired one bead one compound libraries

ACS combinatorial science, 2012

Combinatorial libraries of peptoids (oligo-N-substituted glycines) have proven to be useful sources of protein ligands. Each unit of the peptoid oligomer is derived from 2-haloacetic acid and a primary amine. To increase the chemical diversity available in peptoid libraries, we demonstrate here that heterocyclic halomethyl carboxylic acids can be employed as backbone building blocks in the synthesis of peptoid-based oligomers. Optimized conditions are reported that allow the creation of large, high quality combinatorial libraries containing these units.

Solution effects on the self‐association of a water‐soluble peptoid

Biopolymers, 2018

A desire to replicate the structural and functional complexity of proteins with structured, sequence-specific oligomers motivates study of the structural features of water-soluble peptoids (N-substituted glycine oligomers). Understanding the molecular-level details of peptoid selfassembly in water is essential to advance peptoids' application as novel materials. Peptoid 1, an amphiphilic, putatively helical peptoid previously studied in our laboratory, shows evidence of self-association in aqueous solution. In this work, we evaluate how changes to aqueous solution conditions influence the self-association of 1. We report that changes to pH influence the fluorescence and CD spectroscopic features as well as the peptoid's interaction with a solvatochromic fluorophore and its apparent size as estimated by size exclusion chromatography. Addition of guanidine hydrochloride and ammonium sulfate also modulate spectroscopic features of the peptoid, its interaction with a solvatochromic fluorophore, and its elution in size exclusion chromatography. These data suggest that the ordering of the self-assembly changes in response to pH and with solvent additives and is more ordered at higher pH and in the presence of guanidine hydrochloride. The deeper understanding of the self-association of 1 afforded by these studies informs the design of new stimuli-responsive peptoids with stable tertiary or quaternary structures.

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Peptoids: a modular approach to drug discovery

Proceedings of the National Academy of Sciences of the United States of America, 1992

Peptoids, oligomers of N-substituted glycines, are described as a motif for the generation of chemically diverse libraries of novel molecules. Ramachandran-type plots were calculated and indicate a greater diversity of conformational states available for peptoids than for peptides. The monomers incorporate t-butyl-based side-chain and 9-fluorenylmethoxy-carbonyl alpha-amine protection. The controlled oligomerization of the peptoid monomers was performed manually and robotically with in situ activation by either benzotriazol-1-yloxytris(pyrrolidino)phosphonium hexafluorophosphate or bromotris(pyrrolidino)phosphonium hexaflurophosphate. Other steps were identical to peptide synthesis using alpha-(9-fluorenylmethoxycarbonyl)amino acids. A total of 15 monomers and 10 oligomers (peptoids) are described. Preliminary data are presented on the stability of a representative oligopeptoid to enzymatic hydrolysis. Peptoid versions of peptide ligands of three biological systems (bovine pancreati...

Sequence Changes Modulate Peptoid Self-Association in Water

Frontiers in Chemistry, 2020

Peptoids, N-substituted glycine oligomers, are a class of diverse and sequence-specific peptidomimetics with wide-ranging applications. Advancing the functional repertoire of peptoids to emulate native peptide and protein functions requires engineering peptoids that adopt regular secondary and tertiary structures. An understanding of how changes to peptoid sequence change structural features, particularly in water-soluble systems, is underdeveloped. To address this knowledge gap, five 15-residue water-soluble peptoids that include naphthalene-functionalized side chains were designed, prepared, and subjected to a structural study using a palette of techniques. Peptoid sequence designs were based on a putative amphiphilic helix peptoid bearing structure-promoting (S)-N-(1-naphthylethyl)glycine residues whose self-association in water has been studied previously. New peptoid variants reported here include sequence changes that influenced peptoid conformational flexibility, functional group patterning (amphiphilicity), and hydrophobicity. Peptoid structures were evaluated and compared using circular dichroism spectroscopy, fluorescence spectroscopy, and size exclusion chromatography. Spectral data confirmed that sequence changes alter peptoids' degree of assembly and the organization of self-assembled structures in aqueous solutions. Insights gained in these studies will inform the design of new water-soluble peptoids with regular structural features, including desirable higher-order (tertiary and quaternary) structural features.

Length and Charge of Water-Soluble Peptoids Impact Binding to Phospholipid Membranes

The Journal of Physical Chemistry B, 2019

In this study, we provide a quantitative description of the adsorption of water-soluble N-substituted glycine oligomers (peptoids) to supported lipid bilayers that mimic mammalian plasma membranes. We prepared a small array of systematically varied peptoid sequences ranging in length from 3 to 15 residues. Using the nonlinear optical method second harmonic generation (SHG), we directly monitored adsorption of aqueous solutions of 3-and 15-residue peptoids to phospholipid membranes of varying physical phase, cholesterol content, and head group charge in physiologically relevant pH buffer conditions without the use of extrinsic labels. Equilibrium binding constants and relative surface coverages of adsorbed peptoids were determined from fits to the Langmuir model. Three-and 15-residue peptoids did not interact with cholesterol-containing lipids or charged lipids in the same manner, suggesting that a peptoid's adsorption mechanism changes with sequence length. In a comparison of four three-residue peptoids, we observed a correlation between equilibrium binding constants and calculated log D 7.4 values. Cationic charge modulated surface coverage. Principles governing how peptoid sequence and membrane composition alter peptoid−lipid interactions may be extended to predict physiological effects of peptoids used as therapeutics or as coatings in medical devices.

Peptoid residues and ?-turn formation

Journal of Peptide Science, 2002

A set of terminally protected tripeptoids containing a residue of either N-methylglycine or N-isobutylglycine in position i + 1/i + 2 were synthesized and tested for intramolecularly H-bonded β-turn formation. By exploiting FT-IR absorption and 1H NMR techniques, their folding tendencies were compared with those of a variety of reference peptides. The amount of β-turn induction and the relative extent of the various types of intramolecularly H-bonded β-turn conformers were determined in chloroform solution. Copyright © 2002 European Peptide Society and John Wiley & Sons, Ltd.

In Vivo, In Vitro, and In Silico Characterization of Peptoids as Antimicrobial Agents

PloS one, 2016

Bacterial resistance to conventional antibiotics is a global threat that has spurred the development of antimicrobial peptides (AMPs) and their mimetics as novel anti-infective agents. While the bioavailability of AMPs is often reduced due to protease activity, the non-natural structure of AMP mimetics renders them robust to proteolytic degradation, thus offering a distinct advantage for their clinical application. We explore the therapeutic potential of N-substituted glycines, or peptoids, as AMP mimics using a multi-faceted approach that includes in silico, in vitro, and in vivo techniques. We report a new QSAR model that we developed based on 27 diverse peptoid sequences, which accurately correlates antimicrobial peptoid structure with antimicrobial activity. We have identified a number of peptoids that have potent, broad-spectrum in vitro activity against multi-drug resistant bacterial strains. Lastly, using a murine model of invasive S. aureus infection, we demonstrate that one...

Hydrophobic interactions modulate antimicrobial peptoid selectivity towards anionic lipid membranes

Biochimica et Biophysica Acta (BBA) - Biomembranes, 2018

A B S T R A C T Hydrophobic interactions govern specificity for natural antimicrobial peptides. No such relationship has been established for synthetic peptoids that mimic antimicrobial peptides. Peptoid macrocycles synthesized with five different aromatic groups are investigated by minimum inhibitory and hemolytic concentration assays, epi-fluorescence microscopy, atomic force microscopy, and X-ray reflectivity. Peptoid hydrophobicity is determined using high performance liquid chromatography. Disruption of bacterial but not eukaryotic lipid membranes is demonstrated on the solid supported lipid bilayers and Langmuir monolayers. X-ray reflectivity studies demonstrate that intercalation of peptoids with zwitterionic or negatively charged lipid membranes is found to be regulated by hydrophobicity. Critical levels of peptoid selectivity are demonstrated and found to be modulated by their hydrophobic groups. It is suggested that peptoids may follow different optimization schemes as compared to their natural analogues.

Peptide sequence determination of peptidosteroids on a single bead by electrospray ionization-mass spectroscopy

Journal of Separation Science, 2002

Peptide sequence determination of peptidosteroids on a single bead by electrospray ionization-mass spectroscopy An electrospray ionization mass spectroscopy (ESI-MS n ) method has been developed to simultaneously determine the sequence of two strands of tripeptides attached to a steroid-like scaffold. The peptidosteroid compounds were synthesized by solidphase chemistry on TentaGel beads. The sequence of both peptide strands of a compound originating from a single bead could be determined. High-performance liquid chromatography hyphenated to MS n was also applied to a mixture of two isomeric peptidosteroids for sequence determination of their peptide chains.

α-Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference forcis-Amide Bonds

Chemistry - A European Journal, 2017

α-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis-/trans-amide bond conformers, which contribute to the high flexibility of α-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Here we have performed the first thorough analysis of the folding propensities of α-aminoxy peptoids (or N-substituted 2-aminoxyacetic acid oligomers). To this end, the amide bond geometry and conformational properties of a series of model α-aminoxy peptoids were investigated using 1D and 2D NMR experiments, X-ray crystallography, NBO analysis, CD spectroscopy, and MD simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix. Given their ease of synthesis and conformational properties, α-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity.

Structural characterization of a peptoid with lysine-like side chains and biological activity using NMR and computational methods

Organic & Biomolecular Chemistry, 2013

N-Substituted glycine oligomers or peptoids with charged side chains are a novel class of cell penetrating peptide mimetics and have been shown to serve as drug delivery agents. Here, we investigated by NMR spectroscopy and quantum chemical calculations whether a Rhodamine B labelled peptoid [RhoB Spiro -Ahx]-[But] 6A NH 2 with lysine-like side chains adopts structural motifs similar to regular peptides. Due to a low chemical shift dispersion, high resolution structure determination with conventional NMR-derived distance restraints and J-couplings was not possible. Instead, a combined assignment and structure refinement strategy using the QM/MM force field COSMOS-NMR was developed to interpret the highly ambiguous chemical shift and distance constraints and obtain a medium resolution three-dimensional structural model. This allowed us to select for the all cis-amide conformation of the peptide with a pseudo-helical arrangement of extended side chains as a faithful representative structure of [RhoB Spiro -Ahx]-[But] 6A NH 2 . We tested the biological activity of the peptoid by live-cell imaging, which showed that the cellular uptake of the peptoid was comparable to conventional cell-penetrating peptides.

Understanding Sequence Contributions to Peptoid–lipid Interactions: Using Peptoids as a Platform to Advance Multidisciplinary Research and Undergraduate Education in Parallel (original) (raw)

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