Selective Dynamic Assembly of Disulfide Macrocyclic Helical Foldamers with Remote Communication of Handedness

Disulfide bridge formation was investigated in helical aromatic oligoamide foldamers. Depending on the position of thiol‐bearing side chains, exclusive intramolecular or intermolecular disulfide bridging may occur. The two processes are capable of self‐sorting, presumably by dynamic exchange. Quantitative assessment of helix handedness inversion rates showed that bridging stabilizes the folded structures. Intermolecular disulfide bridging serendipitously yielded a well‐defined, C₂‐symmetrical, two‐helix bundle‐like macrocyclic structure in which complete control over relative handedness, that is, helix–helix handedness communication, is mediated remotely by the disulfide bridged side chains in the absence of contacts between helices. MM calculations suggest that this phenomenon is specific to a given side chain length and requires disulfide functions     

Extraordinarily robust polyproline type I peptoid helices generated via the incorporation of α-chiral aromatic N-1-naphthylethyl side chains

Peptoids, or oligomers of N-substituted glycines, are a class of foldamers that have shown extraordinary functional potential since their inception nearly two decades ago. However, the generation of well-defined peptoid secondary structures remains a difficult task. This challenge is due, in part, to the lack of a thorough understanding of peptoid sequence-structure relationships and, consequently, an incomplete understanding of the peptoid folding process. We seek to delineate sequence-structure relationships through the systematic study of noncovalent interactions in peptoids and the design of novel amide side chains capable of such interactions. Herein, we report the synthesis and detailed structural analysis of a series of (S)-N-(1-naphthylethyl)glycine (Ns1npe) peptoid homo-oligomers by X-ray crystallography, NMR spectroscopy, and circular dichroism (CD) spectroscopy. Four of these peptoids were found to adopt well-defined structures in the solid state, with dihedral angles similar to those observed in polyproline type I (PPI) peptide helices and in peptoids with α-chiral side chains. The X-ray crystal structure of a representative Ns1npe tetramer revealed an all cis-amide helix, with approximately three residues per turn, and a helical pitch of approximately 6.0 ?. 2D-NMR analysis of the length-dependent Ns1npe series showed that these peptoids have very high overall backbone amide K(cis/trans) values in acetonitrile, indicative of conformationally homogeneous structures in solution. Additionally, CD spectroscopy studies of the Ns1npe homo-oligomers in acetonitrile and methanol revealed a striking length-dependent increase in ellipticity per amide. These Ns1npe helices represent the most robust peptoid helices to be reported, and the incorporation of (S)-N-(1-naphthylethyl)glycines provides a new approach for the generation of stable helical structure in this important class of foldamers.     

Influence of linkage chemistry on folding,self-assembly,and photoresponse of amphiphilic azobenzene main chain polymers

Two types of amphiphilic polymers composed of azobenzene repeat units in the main chain connected either via ethynylene (acetylene) or butadiynylene (diacetylene) linkages and carrying oligo(ethylene glycol) side chains were reported. Synthesis was accomplished by polycondensation involving Sonogashira–Hagihara cross coupling and Glaser coupling, respectively. Solvent titration experiments revealed that both polymers fold into stable helices in a polar environment. While the ethynylene-bridged polymer resembled the behavior of its oligomeric counterparts, introduction of the extended diacetylene unit strengthened π,π-stacking interactions in case of the butadiynylene-bridged polymer leading to a pronounced aggregation tendency and suppressing photoisomerization in the folded state. Our study demonstrates the importance of backbone connectivity to balance intra- and intermolecular forces for the successful design of photoresponsive polymers. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 313–318     

Helical Folding of Conjugated Oligo(phenyleneethynylene): Chain‐Length Dependence,Solvent Effects,and Intermolecular Assembly

As a representative folding system that features a conjugated backbone, a series of monodispersed (o‐phenyleneethynylene)‐alt‐(p‐phenyleneethynylene) (PE) oligomers of varied chain length and different side chains were studied. Molecules with the same backbone but different side‐chain structures were shown to exhibit similar helical conformations in respectively suitable solvents. Specifically, oligomers with dodecyloxy side chains folded into the helical structure in apolar aliphatic solvents, whereas an analogous oligomer with tri(ethylene glycol) (Tg) side chains adopted the same conformation in polar solvents. The fact that the oligomers with the same backbone manifested a similar folded conformation independent of side chains and the nature of the solvent confirmed the concept that the driving force for folding was the intramolecular aromatic stacking and solvophobic interactions. Although all were capable of inducing folding, different solvents were shown to bestow slightly varied folding stability. The chain‐length dependence study revealed a nonlinear correlation between the folding stability with backbone chain length. A critical size of approximately 10 PE units was identified for the system, beyond which folding occurred. This observation corroborated the helical nature of the folded structure. Remarkably, based on the absorption and emission spectra, the effective conjugation length of the system extended more effectively under the folded state than under random conformations. Moreover, as evidenced by the optical spectra and dynamic light‐scattering studies, intermolecular association took place among the helical oligomers with Tg side chains in aqueous solution. The demonstrated ability of such a conjugated foldamer in self‐assembling into hierarchical supramolecular structures promises application potential for the system.     

Helical (isotactic) and syndiotactic silver(I) metallo-supramolecular coordination polymers assembled from a readily prepared bis-pyridylimine ligand containing a 1,5-naphthalene spacer

A ligand in which two pyridylimine binding units are linked by a 1,5-naphthalene spacer is prepared and its silver(I) coordination chemistry investigated. In the solid state, a pair of C-H triplebond N interactions between pyridylimine units link the free ligands into chain structures, with further C-H triplebond N and some -stacking interactions linking these chains into a three-dimensional structure. The spacer constrains the ligand to dinucleate, and with silver(I) the metal coordinates to two pyridylimine units from two separate ligands and this leads to the formation of coordination polymers with a range of different anions. Different twisting motifs within the ligand control the tacticity of these coordination polymers and both isotactic, helical polymers and syndiotactic (achiral) polymers result. The core of the isotactic polymer strands contains two metallo-vectors and results in long-range ordering of the metal centres into a 2 x n grid arrangement. The solution behaviour indicates that exchange between the diastereomeric forms occurs. Since this must involve inversion at the metal centres, atactic species may also form a component of the solution library.     

Artificial chemokines: combining chemistry and molecular biology for the elucidation of interleukin-8 functionality

How can we understand the contribution of individual parts or segments to complex structures? A typical strategy to answer this question is simulation of a segmental replacement followed by realization and investigation of the resulting effect in structure-activity studies. For proteins, this problem is commonly addressed by site-directed mutagenesis. A more general approach represents the exchange of whole secondary structure elements by rationally designed segments. For a demonstration of this possibility we identified the alpha-helix at the C-terminus of human interleukin-8 (hIL-8). Since this chemokine possesses four conserved cysteine residues, it can easily be altered by ligation strategies. A set of different segments, which are able to form amphiphilic helices, was synthesized to mimic the C-terminal alpha-helix. Beside sequences of alpha-amino acids, oligomers of non-natural beta(3)-amino acids with the side chains of canonical amino acids were introduced. Such beta-peptides form helices, which differ from the alpha-helix in handedness and dipole orientation. Variants of the semisynthetic hIL-8 proteins demonstrated clearly that the exact side chain orientation is of more importance than helix handedness and dipole orientation. The activity of a chimeric protein with a beta-peptide helix that mimics the side chain orientation of the native alpha-helix most perfectly is comparable to that of the native hIL-8. Concepts like this could be a first step toward the synthesis of proteins consisting of large artificial secondary structure elements.     

Conformations produced by interactions of the side chains in poly(silylenemethylene) with the repeating sequence [Si(CH3)R?CH2]x [R = ?O(CH2)3OC6H4C6H5]

A coarse-grained model has been developed for asymmetrically substituted poly(silylenemethylene)s in which the side chain is a flexible spacer terminated by a biphenyl unit. Each monomer unit is represented by four coarse-grained beads that interact via a Lennard–Jones potential and are subject to the first- and second-order interactions deduced from the atomistically detailed model. Metropolis Monte Carlo simulations were performed for isolated syndiotactic, isotactic, and atactic chains. Snapshots from the equilibrated coarse-grained chain on the discrete space of a high coordination lattice were reverse-mapped to atomistically detailed structures in continuous space. At 373 K, the chains were disordered independent of the stereochemical composition. The occupancy of bond pairs depended on the stereochemical composition, with the trans-gauche (tg) sequence being favored by the isotactic chain. When the simulation was performed with the backbone constrained to specific periodic structures, the g helix was the lowest energy structure for either the atactic or isotactic chains. For the syndiotactic chain, the g and gt helices were favored. The appearance of the g helix as the favored periodic structure of the isolated chain was consistent with the chain conformation reported previously for the smectic phase of this polymer in the bulk state. The g helix was disrupted when the backbone was allowed to access nonhelical conformations, even though these conformations may have been slightly higher in energy. © 2005 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 43: 886–896, 2005     

Two- and three-dimensional smectic ordering of single-handed helical polymers

Rodlike polymers with precisely defined architectures are ideal building blocks for self-assembled structures leading to novel nanometer-scale devices. We found that the living polymerization of a single isocyanide enantiomer bearing an l-alanine pendant with a long n-decyl chain simultaneously produced diastereomeric right- and left-handed helices with different molecular weights and narrow molecular weight distributions. Each single-handed, rodlike helical polymer with a controlled length and handedness isolated by a facile solvent fractionation method with acetone self-assembled to form well-defined two- and three-dimensional smectic ordering on the nanometer scale on a substrate and in a liquid crystalline state as evidenced by direct atomic force microscopic observations and X-ray diffraction measurements, respectively.     

Foldamers to Nanotubes: Influence of Amino Acid Side Chains in the Hierarchical Assembly of α,γ4‐Hybrid Peptide Helices

Supramolecular assembly of various artificially folded 12‐helical architectures composed of γ⁴‐Val, γ⁴‐Leu and γ⁴‐Phe residues is investigated. In contrast to the 12‐helices composed of γ⁴‐Val and γ⁴‐Leu residues, the helices with γ⁴‐Phe residues displayed unique elongated nanotubular architectures. The elongated nanotube assembly was further explored as a template for biomineralization of silver ions to silver nanowires. A comparative study using an analogous α‐peptide helix reveals the importance of the spatial arrangement of aromatic side chains along the helical cylinder in a 12‐helix. These results suggested that the proteolytically and structurally stable α,γ⁴‐hybrid peptide 12‐helices may serve as a new generation of potential templates in the design of functional biomaterials.     

Switching of chiral induction in helical aromatic oligoamides using solid state-solution state equilibrium

The introduction of an R asymmetric center in an aromatic oligoamide that adopts stable helical conformations leads to a significant shift of the equilibrium between the right-handed and left-handed helices in solution: the R-P and R-M helices are diastereoisomers. However, these two species were found to cocrystallize in 1:1 proportions. Thus the chiral induction observed in solution is switched off in the solid state. This phenomenon represents an original and unexpected means to control handedness in helical oligomers.     

Effects of hydrophobic and dipole-dipole interactions on the conformational transitions of a model polypeptide

We studied the effects of hydrophobicity and dipole-dipole interactions between the nearest-neighbor amide planes on the secondary structures of a model polypeptide by calculating the free energy differences between different peptide structures. The free energy calculations were performed with low computational costs using the accelerated Monte Carlo simulation (umbrella sampling) method, with a bias-potential method used earlier in our accelerated molecular dynamics simulations. It was found that the hydrophobic interaction enhances the stability of alpha helices at both low and high temperatures but stabilizes beta structures only at high temperatures at which alpha helices are not stable. The nearest-neighbor dipole-dipole interaction stabilizes beta structures under all conditions, especially in the low temperature region where alpha helices are the stable structures. Our results indicate clearly that the dipole-dipole interaction between the nearest neighboring amide planes plays an important role in determining the peptide structures. Current research provides a more unified and quantitative picture for understanding the effects of different forms of interactions on polypeptide structures. In addition, the present model can be extended to describe DNA/RNA, polymer, copolymer, and other chain systems.     

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

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 alpha-helical structures. Yet, when peptoids are N-substituted with alpha-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 alpha-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% alpha-chiral, aromatic residues is necessary for the formation of stable helical structure in hexameric sequences. Moreover, both CD and 1H-13C HSQC NMR studies reveal that these short peptoid helices are stabilized by the placement of an alpha-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 alpha-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.     

Design of an inversion center between two helical segments

A new strategy is proposed to control the relative orientation of two folded helical oligomers in such a way that they diverge from an aromatic linker and have opposite helical handedness. Mutual steric exclusion between the two helices results from the fact that they cannot be at the same time folded and on the same side of the linker. The concept is validated using the helical conformations of oligoamides of 8-amino-2-quinolinecarboxylic acid, but it should be applicable to many families of oligomers and leads to the first designed meso-helices.     

Double versus single helical structures of oligopyridine-dicarboxamide strands. Part 2: The role of side chains

A series of heptameric oligoamides comprising 4-alkoxy-substituted 2,6-diaminopyridine and 2,6-pyridine-dicarbonyl units have been synthesized using convergent methods. The hybridization of these compounds into double helical dimers was studied in solution by ¹H NMR spectroscopy in CDCl₃ or DMSO-d₆ at various concentrations, and in the solid state using X-ray crystallographic analysis. Both solid state and solution data suggest that these compounds follow identical hybridization schemes. In CDCl₃, the oligomers possess dimerization constants considerably (up to 2000-fold) higher than related compounds having no alkoxy substituents on their 2,6-diaminopyridine units. The origin of this effect can be in part interpreted as a result of interactions between the 4-alkoxy side chains when they are present on all pyridine rings. For example, 4-benzyloxy-substituted oligomer 2 has a higher dimerization constant than 4-decyloxy and 4-methoxy-substituted analogues 1 and 3. The crystal structure of 2 reveals multiple aromatic-aromatic interactions between the benzyl side chains, both face-to-face and edge-to-face at various angles surrounding the duplex. In the solid state, these double helices are stacked on top of each other to form long channels filled with water molecules. The 4-methoxy and 4-decyloxy-substituted analogues 1 and 3 have similar dimerization constants, showing that interactions between side chains are not significant between purely aliphatic residues. Consequently, the high stability of the double helices formed by 1 and 3 compared to related compounds having alkoxy substituents on their 2,6-pyridine-dicarbonyl units only does not find its origin in interactions between side chains but in the direct effect of the alkoxy substituents upon main chain aryl-aryl interactions.     

Distinct M and P helical complexes of H2O and metal ions NiII, CuII, and ZnII with enantiomerically pure chiral bis(pyrrol-2-ylmethyleneamine)cyclohexane ligands: crystal structures and circular dichroism properties

The enantiomerically pure bis-bidentate ligands of bis(pyrrol-2-ylmethyleneamine)cyclohexane [H2(LR,S)] are easily synthesized from condensation of the pure R,R and S,S enantiomers of the 1,2-diaminecyclohexane spacer with 2 equiv of pyrrole-2-carbaldehyde. The coordination of [H2(LR,S)] with a H2O molecule and metal ions NiII, CuII, and ZnII gives rise to distinct helical structures and crystal packing motifs: homochiral and enantiopure infinite single-helical polymeric chains of [(H2(LR,S).H2O)n] via hydrogen bonds, mononuclear single helices of [NiII(LR,S)] and [CuII(LR,S)], and a double-stranded dinuclear helicate of [ZnII2(LR,S)2], respectively. The helical structures for all metal complexes in the solid state still remain in the solution. Remarkably, chiral ligands of [H2(LR)] and [H2(LS)] predetermine the chirality of the helices and helicates, i.e., P left-handedness and M right-handedness, respectively. The structural changes of these complexes induced by different coordinators are also characterized by circular dichroism (CD) and absorption spectra in both the solid state and solution. Analysis of CD spectra, with aids of absolute determination of single-crystal X-ray diffraction structures, reveals both intraligand and interligand chromophore couplings. For the potential applications of these complexes, other experiments such as magnetism, photoluminescence, and nonlinear optical properties have also been investigated.     

alpha and piDL helical states of alternating poly(gamma-benzyl D-L-glutamate) in solution.

As in solid state, strictly alternating poly(gamma-benzyl D-L-glutamate) in solution can adopt two different helical conformations. Besides the alpha helix, a second helical conformation is found at higher temperatures in dioxane and chloroform, the properties of which correspond to that of the piDL4 helix. As the molecules have a finite length a screw sense is favored for both helical forms thus giving rise to optical activity allowing the study of the transconformation by optical rotatory dispersion and circular dichroism besides infrared and dielectric measurements. Thus, as the temperature is raised the equilibria right-left handed alpha helices and alpha-piDL helical forms can be followed. The favored screw senses are determined by the number of interacting side chains for the alpha helix and by the number of hydrogen bonds which are formed in the piDL helical conformation. The side chain-side chain interactions in the alpha helix are experimentally shown to be attractive.     

Amphipathic helices from aromatic amino acid oligomers

Synthetic helical foldamers are of significant interest for mimicking the conformations of naturally occurring molecules while at the same time introducing new structures and properties. In particular, oligoamides of aromatic amino acids are attractive targets, as their folding is highly predictable and stable. Here the design and synthesis of new amphipathic helical oligoamides based on quinoline-derived amino acids having either hydrophobic or cationic side chains are described. Their structures were characterized in the solid state by single-crystal X-ray diffraction and in solution by NMR. Results of these studies suggest that an oligomer as short as a pentamer folds into a stable helical conformation in protic solvents, including MeOH and H(2)O. The introduction of polar proteinogenic side chains to these foldamers, as described here for the first time, promises to provide possibilities for the biological applications of these molecules. In particular, amphipathic helices are versatile targets to explore due to their importance in a variety of biological processes, and the unique structure and properties of the quinoline-derived oligoamides may allow new structure-activity relationships to be developed.     

螺旋聚(N-炔丙基酰胺)的合成及侧基对螺旋结构稳定性影响

设计并合成了3种带有不同侧基的N-炔丙基酰胺单体(1~3),以红外、核磁、元素分析等技术对单体进行了表征;以[Rh]金属有机配合物为催化剂实施聚合反应得到高产率(近100%)的聚合物,聚合物具有高的立构规整性.利用紫外吸收谱图对聚合物的二级结构进行了表征,聚合物1与聚合物3分别在羰基的α和γ位有支链,聚合物不易形成螺旋结构;聚合物2在羰基的β位有支链,聚合物易于形成稳定的螺旋结构.表明相邻侧链上酰胺基团间形成的氢键及侧链间适当的空间位阻是聚合物形成稳定螺旋的关键因素.     

Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution

In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right‐handed and left‐handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer–protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 Å resolution and revealed a number of unanticipated protein–foldamer, foldamer–foldamer, and protein–protein interactions.     

Chiroptical Helices of N-Terminal Aryl Amino Acids through Orthogonal Noncovalent Interactions

In the solid state, amino acids (alanine and phenylglycine) with appended pyrene segments self-assembled into α-helix-like structures by asymmetrical H-bonds between carboxylic acid and amide segments, further inducing supramolecular tilted chirality of the achiral pyrenes. These structures bind melamine and electron-deficient units through H-bond and charge-transfer interactions, respectively. Charge-transfer interactions enhance the dissymmetry g-factor of absorption (g_abs; up to 1.4×10⁻²) with an extended Cotton effect active region (from 250 to 600 nm). Incorporating melamine inverts the handedness of circularly polarized luminescence and boosts the dissymmetry g-factor (g_lum). Melamine also induces macroscopic chirality at the nanoscale, whereby the 2D lamellar structures are transformed into 1D helices at the nanoscale, leading to giant tubular structures at the microscale.