Self-assembly of folded m-phenylene ethynylene oligomers into helical columns

Circular dichroism spectroscopy has been used to study the self-assembly of two series of m-phenylene ethynylene oligomers in highly polar solvents. The helical conformation of shorter oligomer lengths was found to be stabilized in aqueous acetonitrile solutions, while longer oligomers began to interact intermolecularly. The intermolecular aggregation of the oligomers in aqueous solutions revealed a chain length dependent association that required the presence of a stable helical conformation. Evidence for intermolecular interactions is provided by Sergeants and Soldiers experiments in which the twist sense bias of a chiral oligomer is transferred to an achiral oligomer.     

Twist Sense Bias Induced by Chiral Side Chains in Helically Folded Oligomers

Cooperative interactions among the side chains of the helically folded phenylene-ethynylene oligomer shown (n=2, 4, 6, 8, 10, 12, 14, 16, 18) can induce a twist sense bias. Therefore, the side chains can play more than just an ancillary role in these conformationally ordered oligomers. The onset of the twist sense bias lags significantly behind the appearance of helical conformations, possibly because a large ensemble of "collapsed" conformations is initially formed.     

Guest‐Induced Arylamide Polymer Helicity: Twist‐Sense Bias and Solvent‐Dependent Helicity Inversion

A benzene/naphthalene alternately incorporated amide polymer was synthesized and characterized. ¹H NMR spectroscopy, fluorescence, and circular dichroism (CD) experiments indicated that, in chloroform, the polymer could be induced by the chiral l ‐aspartic acid dianion or one of its derivatives to form a helical tubular conformation with twist‐sense bias. CD titration studies showed that the l ‐aspartic acid dianion (8 equiv.) could lead to a maximum Cotton effect. It was also revealed that the twist‐sense bias obeyed the majority rule, and 70 % enantiomeric excess could realize the maximum helicity bias. Adding acetonitrile to the solution of chloroform caused inversion of the guest‐induced helicity bias of the polymer.     

Helical twist sense bias in oligo(phenylene ethynylene)s induced by an optically active flexible tether

[graph and structure: see text] A series of tethered phenylene ethynylene oligomers, which undergo a solvent-dependent conformational transition from a random coil to a helix, has been synthesized. The use of trimethylsilyl ether protecting groups on the (+)-tartaric acid-derived tether results in the formation of helices with a large twist sense bias. In contrast, an isopropylidene ketal protecting group or no protecting group is not only ineffective at helical discrimination but may even inhibit helix formation.     

A helicene-containing foldamer displaying highly solvent-dependent CD spectra

[structure: see text] A m-phenylene ethynylene oligomer containing a helicene unit was synthesized to bias the twist sense of the folded helical conformation. The CD spectra of the helicene oligomer exhibited large Cotton effects that varied greatly with the solvent composition, including three separate conformational transitions.     

Folding and Aggregation of Cationic Oligo(aryl‐triazole)s in Aqueous Solution

Cationic aryl triazole oligomers have been synthesized through “click chemistry”. The results show that cationic aryl triazole oligomers adopt a helical conformation in water or in a mixture of water and methanol, but prevail as a random‐coiled conformation in methanol. Importantly, circular dichroism spectroscopy and dynamic light scattering experiments revealed that cationic oligomers aggregated intermolecularly to form higher order architectures with a helical sense opposite to that of the individual helix, which eventually led to the formation of aggregates with sizes in the range 100–500 nm. The aggregation of cationic oligomers was governed by the concentration and polarity of the environment. More interestingly, cationic foldamers were able to recognize chloride and fluoride anions in aqueous solution. The recognition consequently destabilized intermolecular aggregation.     

Homo-N-oligonucleotides (N1/N9-C1' methylene bridge oligonucleotides): nucleic acids with left-handed helicity

Oligonucleotides containing a methylene bridge between N1 or N9 of the heterocyclic base and C1' of the pentofuranosyl ring (homo-N-oligonucleotides) were synthesized. Melting curves revealed that such homo-type oligomers could cross-pair with complementary homo-type or natural oligomers. Circular-dichroic studies provide evidence that the homo-type dimers have a left-handed stacked conformation and further suggest that single-stranded and double-stranded homo-type oligomers adopt a left-handed conformation, while duplexes with natural oligomers or nucleic acids form RNA-like right-handed helices. NMR spectroscopy (NOESY) provides supporting evidence for a left-handed stacked conformation of the homo-type dimer, while atomic force microscopy indicates a left-handed helical conformation of homo-type dsDNA. Homo-type dimers and oligomers showed high resistance to digestion by snake-venom and calf-spleen phosphodiesterases and nuclease S1.     

The N‐Terminal Nonapeptide of Cephaibols A and C: A Naturally Occurring Example of Mismatched Helical Screw‐Sense Control

The N‐terminal nonapeptide domain of the fungal nonribosomal peptide antibiotics cephaibol A and cephaibol C (AcPheAib₄LeuIvaGly‐ Aib) is reported to adopt a right‐handed helical conformation in the crystalline state. However, this conformation is at odds with the left‐handed helicity observed in solution in related synthetic oligomers capped with Ac‐L ‐PheAib₄ fragments. We report the synthesis of four diastereoisomers of the cephaibol N‐terminal nonapeptide, and show by NMR and CD spectroscopy that the peptide containing the chiral amino acids Phe and Leu in the naturally occurring relative configuration exists in solution as an interconverting mixture of helical screw‐sense conformers. In contrast, the nonapeptide containing the unnatural relative configuration at Phe and Leu adopts a single, stable helical screw‐sense, which is left handed when the N‐terminal Phe residue is L and right‐handed when the N‐terminal Phe residue is D .     

Probing the role of the C-H...O hydrogen bond stabilized polypeptide chain reversal at the C-terminus of designed peptide helices. Structural characterization of three decapeptides

The structural characterization in crystals of three designed decapeptides containing a double d-segment at the C-terminus is described. The crystal structures of the peptides Boc-Leu-Aib-Val-Xxx-Leu-Aib-Val-(D)Ala-(D)Leu-Aib-OMe, (Xxx = Gly 2, (D)Ala 3, Aib 4) have been determined and compared with those reported earlier for peptide 1 (Xxx = Ala) and the all l analogue Boc-Leu-Aib-Val-Ala-Leu-Aib-Val-Ala-Leu-Aib-OMe, which yielded a perfect right-handed alpha-helical structure. Peptides 1 and 2 reveal a right-handed helical segment spanning residues 1 to 7, ending in a Schellman motif with (D)Ala(8) functioning as the terminating residue. Polypeptide chain reversal occurs at residue 9, a novel feature that appears to be the consequence of a C-H.O hydrogen bond between residue 4 C(alpha)H and residue 9 CO groups. The structures of peptides 3 and 4, which lack the pro R hydrogen at the C(alpha) atom of residue 4, are dramatically different. Peptide 3 adopts a right-handed helical conformation over the 1 to 7 segment. Residues 8 and 9 adopt alpha(L) conformations forming a C-terminus type I' beta-turn, corresponding to an incipient left-handed twist of the polypeptide chain. In peptide 4, helix termination occurs at Aib(6), with residues 6 to 9 forming a left-handed helix, resulting in a structure that accommodates direct fusion of two helical segments of opposite twist. Peptides 3 and 4 provide examples of chiral residues occurring in the less favored sense of helical twist; (D)Ala(4) in peptide 3 adopts an alpha(R) conformation, while (L)Val(7) in 4 adopts an alpha(L) conformation. The structural comparison of the decapeptides reported here provides evidence for the role of specific C-H.O hydrogen bonds in stabilizing chain reversals at helix termini, which may be relevant in aligning contiguous helical and strand segments in polypeptide structures.     

(24R)‐24,25‐Dihydroxycyclo­artan‐3‐one

In the title compound, C₃₀H₅₀O₃, the three six‐membered rings adopt chair, twist and twist‐boat conformations. The five‐membered ring is in a slightly distorted envelope conformation. The substituent on the five‐membered ring is in an extended conformation, with its two hydroxyl O atoms forming an intramolecular hydrogen bond. One of these O atoms also forms an intermolecular hydrogen bond with the oxy­gen of the carbonyl group in a neighbouring mol­ecule.     

Synthesis, structure, and nonlinear optical properties of cross-conjugated perphenylated iso-polydiacetylenes

Monodisperse, cross-conjugated perphenylated iso-polydiacetylene (iso-PDA) oligomers, ranging from monomer 15 to pentadecamer 25, have been synthesized by using a palladium-catalyzed cross-coupling protocol. Structural characteristics elucidated by X-ray crystallographic analysis demonstrate a non-planar backbone conformation for the oligomers due to the steric interactions between alkylidene phenyl groups. The electronic absorption spectra of the oligomers show a slight red-shift of the maximum absorption wavelength as the chain length increases from dimer 17 b to pentadecamer 25, a trend that has saturated by the stage of nonamer 22. Fluorescence spectroscopy confirms that the pendent phenyl groups present on the oligomer framework enhance emission, and the relative emission intensity consistently increases as a function of chain length n. The molecular third-order nonlinearities, gamma, for this oligomer series have been measured via differential optical Kerr effect (DOKE) detection and show a superlinear increase as a function of the oligomer chain length n. Molecular modeling and spectroscopic studies suggest that iso-PDA oligomers (n>7) adopt a coiled, helical conformation in solution.     

Effect of DNA hairpin loops on the twist of planar DNA origami tiles

The development of scaffolded DNA origami, a technique in which a long single-stranded viral genome is folded into arbitrary shapes by hundreds of short synthetic oligonucleotides, represents an important milestone in DNA nanotechnology. Recent findings have revealed that two-dimensional (2D) DNA origami structures based on the original design parameters adopt a global twist with respect to the tile plane, which may be because the conformation of the constituent DNA (10.67 bp/turn) deviates from the natural B-type helical twist (10.4 bp/turn). Here we aim to characterize the effects of DNA hairpin loops on the overall curvature of the tile and explore their ability to control, and ultimately eliminate any unwanted curvature. A series of dumbbell-shaped DNA loops were selectively displayed on the surface of DNA origami tiles with the expectation that repulsive interactions among the neighboring dumbbell loops and between the loops and the DNA origami tile would influence the structural features of the underlying tiles. A systematic, atomic force microscopy (AFM) study of how the number and position of the DNA loops influenced the global twist of the structure was performed, and several structural models to explain the results were proposed. The observations unambiguously revealed that the first generation of rectangular shaped origami tiles adopt a conformation in which the upper right (corner 2) and bottom left (corner 4) corners bend upward out of the plane, causing linear superstructures attached by these corners to form twisted ribbons. Our experimental observations are consistent with the twist model predicted by the DNA mechanical property simulation software CanDo. Through the systematic design and organization of various numbers of dumbbell loops on both surfaces of the tile, a nearly planar rectangular origami tile was achieved.     

Enantioselective binding of an 11-cis-locked cyclopropyl retinal. The conformation of retinal in bovine rhodopsin

[formula: see text] The conformation of the retinal chromophore in rhodopsin is central for understanding the visual transduction process. The absolute twist around the 12-s bond of the chromophore in rhodopsin has been determined by studies with 11-cis-locked 11,12-cyclopropylretinal analogues (11S,12R)-2 and (11R,12S)-3, enantioselectively synthesized with the aid of an enzyme. The finding that enantiomer 2 binds to opsin while the other 3 does not defines the absolute sense of twist around the 12-s bond.     

Sequence-structure relationships in DNA oligomers: a computational approach

A collective-variable model for DNA structure is used to predict the conformation of a set of 30 octamer, decamer, and dodecamer oligomers for which high-resolution crystal structures are available. The model combines an all-atom base pair representation with an empirical backbone, emphasizing the role of base stacking in fixing sequence-dependent structure. We are able to reproduce trends in roll and twist to within 5 degrees across a large database of both A- and B-DNA oligomers. A genetic algorithm approach is used to search for global minimum structures and this is augmented by a grid search to identify local minimums. We find that the number of local minimums is highly sequence dependent, with certain sequences having a set of minimums that span the entire range between canonical A- and B-DNA conformations. Although the global minimum does not always agree with the crystal structure, for 24 of the 30 oligomers, we find low-energy local minimums that match the experimental step parameters. Discrepancies throw some light on the role of crystal packing in determining the solid-state conformation of double-helical DNA.     

Noncovalent domino effect on helical screw sense of chiral peptides possessing C-terminal chiral residue

Recently, a novel chiral intermolecular interaction was found in an N-deprotected achiral nonapeptide that undergoes the predominance of one-handed screw sense through the addition of chiral small carboxylic acid (Inai, Y.; Tagawa, K.; Takasu, A.; Hirabayashi, T.; Oshikawa, T.; Yamashita, M. J. Am. Chem. Soc. 2000, 122, 11731). We here clarify to what extent such noncovalent chiral domino effect affects the helical screw sense of an N-deprotected chiral peptide. Two chiral peptides consisting of C-terminal L-Leu (1) or L-Leu(2) (2) and the preceding achiral helical octapeptide segment were employed. NMR and IR spectroscopy, and energy calculation indicated that both peptides adopt a helical conformation in chloroform. Peptide 1 showed a small excess of a left-handed screw sense for the achiral helical octapeptide, but peptide 2 strongly preferred a right-handed screw sense. The addition of chiral Boc amino acid to a chloroform solution of peptide 1, depending on its chirality, underwent a unique helix-to-helix transition or led to remarkable stabilization of the original left-handed screw sense. Peptide 2 retained the original right-handed screw sense on addition of chiral Boc-amino acid, but its helical stability changed to some extent depending on its added chirality. Therefore, the importance of noncovalent domino effect for controlling the helical screw sense or helical stability of a chiral peptide has been demonstrated here for the first time. In addition, we here have presented a unique system that both N-terminal noncovalent and C-terminal covalent domino effects operate simultaneously on the helical screw sense of a single achiral segment and have compared both powers for inducing the screw sense bias.     

Solution and biologically relevant conformations of enantiomeric 11-cis-locked cyclopropyl retinals

To gain information on the conformation of the 11-cis-retinylidene chromophore bound to bovine opsin, the enantiomeric pair (2a and 2b) of 11-cis-locked bicyclo[5.1.0]octyl retinal (retCPr) 2 was prepared and its conformation was investigated by NMR, geometry optimization, and CD calculations. This compound is also of interest since it contains a unique moiety in which a chiral cyclopropyl group is flanked by triene and enal chromophores, and hence would clarify the little-known chiroptical contribution of a cyclopropyl ring linked to polyene systems. NMR revealed that the seven-membered ring of retCPr adopts a twist chair conformation. The NMR-derived structure constraints were then used for optimizing the geometry of 2 with molecular mechanics and ab initio methods. This revealed that enantiomer 2a with a 11 beta,12 beta-cyclopropyl group exists as two populations of diastereomers depending on the twist around the 6-s bond; however, the sense of twist around the 12-s is positive in both rotamers. The theoretical Boltzmann-weighted CD obtained with the pi-SCF-CI-DV MO method and experimental spectra were consistent, thus suggesting that the conjugative effect of the cyclopropyl moiety is minimal. It was found that only the beta-cyclopropyl enantiomer 2a, but not the alpha-enantiomer 2b, binds to opsin. This observation, together with earlier retinal analogues incorporation results, led to the conclusion that the chromophore sinks into the N-terminal of the opsin receptor from the side of the 4-methylene and 15-aldehyde, and that the binding cleft accommodates 11-cis-retinal with a slightly positive twist around C12/C13. A reinterpretation of the previously published negative CD couplet of 11,12-dihydrorhodopsin also leads to a chromophoric C12/C13 twist conformation with the 13-Me in front as in 1b. Such a conformation for the chromophore accounts for both the observed biostereoselectivity of retCPr 2a and the observed negative couplet of 11,12-dihydro-Rh7.     

Dihydrazidophosphoric Acid Derivatives as Starting Materials for Inorganic Heterocycles with Unusual Ring Conformations

Abstract

Reported are synthetic routes to inorganic heterocycles of different ring size, containing phosphorus, hydrazine, silicon and other elements as ring components. Steric effects that cause saturated sixmembered rings to adopt an unusual twist conformation are discussed (temperature dependent NMR-spectra, X-ray structures).     

A helix-turn-helix supersecondary structure based on oligo(phenanthroline dicarboxamide)s

An artificial helix-turn-helix (HTH) supersecondary structure based on the oligo(phenanthroline dicarboxamide)s, in which the 2,2'-dimethoxy-1,1'-binaphthyl-6,6'-diamine subunit was utilized as the turn to impart a bias in the twist sense of the supersecondary structure, was reported. The HTH structure has been demonstrated by UV/vis, NMR, CD spectra, and X-ray crystal analysis.     

Interplay among folding, sequence, and lipophilicity in the antibacterial and hemolytic activities of alpha/beta-peptides

Host-defense peptides inhibit bacterial growth but manifest relatively little toxicity toward eukaryotic cells. Many host-defense peptides adopt alpha-helical conformations in which cationic side chains and lipophilic side chains are segregated to distinct regions of the molecular surface ("globally amphiphilic helices"). Several efforts have been made to develop unnatural oligomers that mimic the selective antibacterial activity of host-defense peptides; these efforts have focused on the creation of molecules that are globally amphiphilic in the preferred conformation. One such endeavor, from our laboratories, focused on helix-forming alpha/beta-peptides, i.e., oligomers containing a 1:1 pattern of alpha- and beta-amino acid residues in the backbone [Schmitt, M. A.; Weisblum, B.; Gellman, S. H. J. Am. Chem. Soc. 2004, 126, 6848-6849]. We found, unexpectedly, that the most favorable biological activity profile was displayed by a "scrambled" sequence, which was designed not to be able to form a globally amphiphilic helix. Here we report new data, involving an expanded set of alpha/beta-peptides, from experiments designed to elucidate the origins of this surprising result. In addition, we evaluate the susceptibility of alpha/beta-peptides to proteolytic degradation. Our results support the hypothesis that the ability to adopt a globally amphiphilic helical conformation is not a prerequisite for selective antibacterial activity. This conclusion represents a significant advance in our understanding of the relationship among molecular composition, conformation, and biological activity. Our results should therefore influence the design of other unnatural oligomers intended to function as antibacterial agents.     

Folding-promoted methylation of a helical DMAP analogue

The methylation rate for a series of pyridine-containing phenylene ethynylene oligomers shows a nonlinear dependence on chain length, with a significant rate enhancement observed for oligomers that adopt a folded, helical conformation. The folded structure provides a microenvironment that lowers the energy barrier for the methylation reaction. Of these noncovalent interactions, the largest stabilization may arise from binding of methyl iodide in the hydrophobic cavity of the folded oligomer, in close proximity to the pyridine nucleophile.