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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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...
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
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.
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.