High-resolution nuclear magnetic resonance studies at 270 MHZ of alternating and random poly(benzyl D,L-glutamates).

The solution conformations of several D,L copoly benzyl glutamates both random and alternating are studied by comparing their NMR spectra in chloroform and also in dioxane and dimethylformamide. The alpha CH chemical shifts characteristic of the alpha helix of strictly alternating DL copolymers in chloroform/0.5% TFA are established (3.65 and 3.82 ppm) and differ from that of the regular alpha helix (3.92 ppm). It is concluded that alternating copolymers prepared by an essentially racemization-free method are completely in the alpha-helical conformation which is characteristic of strictly alternating D-L copolymers, whereas random copolymers are largely regular alpha. The alpha leads to piDL helix/helix transition of an alternating copolymer in dioxane has been monitored and the alpha CH resonance characteristic of the piDL helix is found to be at the unusually low chemical shift of 4.45 ppm.     

Optically Active Polysilylenes: State‐of‐the‐Art Chiroptical Polymers

Controlled synthesis, chiroptical characterization, and manipulation of artificial helical polymers are challenging issues in modern polymer stereochemistry. Although many artificial polymers adopting a preferential screw‐sense helical structure have been investigated, optically active polysilylenes bearing chiral side chains may be among the most suitable to elucidate the inherent nature of the helical structure, since these polymers offer powerful spectroscopic probes as a result of their ideal chromophoric and fluorophoric main chain properties around 300–330 nm. The present paper will review comprehensively the helix‐property‐functionality relationship between side chain structure, global and local main chain conformation, (chir)optical properties, electronic properties, several helical cooperative phenomena, the effects of temperature and solvent polarity, and molecular imaging. This knowledge and understanding of the nature of the polysilylene helix might constitute a bridge between artificial polymers and biopolymers and will assist in designing and controlling new types of helical polymers directed to diverse screw‐sense‐related properties and applications in the future.     

A novel type of optically active helical polymers: Synthesis and characterization of poly(N‐propargylureas)

This article presents two novel artificial helical polymers, substituted polyacetylenes with urea groups in side chains. Poly( 4 ) and poly( 5 ) can be obtained in high yields (≥97%) and with moderate molecular weights (11,000–14,000). Poly( 4 ) contains chiral centers in side chains, and poly( 5 ) is an achiral polymer. Both of the two polymers adopted helical structures under certain conditions. More interestingly, poly( 4 ) exhibited large specific optical rotations, resulting from the predominant one‐handed screw sense. The helical conformation in poly( 5 ) was stable against heat, while poly( 4 ) underwent conformational transition from helix to random coil upon increasing temperature from 0 to 55 °C. Solvents had considerable influence on the stability of the helical conformation in poly( 4 ). The screw sense adopted by the helices was also largely affected by the nature of the solvent. Poly( 4 ‐co‐ 5 )s formed helical conformation and showed large optical rotations, following the Sergeants and Soldiers rule. By comparing the present two polymers (with one ? N? H groups) with the three polymers previously reported (with two ? N? H groups in side chains), the nature of the hydrogen bonds formed between the neighboring urea groups played big roles in the formation of stable helical conformation. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4112–4121, 2008     

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.     

A coarse-grained model for the formation of alpha helix with a noninteger period on simple cubic lattices

Periodicity is an important parameter in the characterization of a helix in proteins. In this work, a coarse-grained model for a homopolypeptide in simple cubic lattices has been extended to build an alpha helix with a noninteger period. The lattice model is based on the bond fluctuation algorithm in which bond lengths and orientations are altered in a quasicontinuous way, and the simulation is performed via dynamic Monte Carlo simulation. Hydrogen bonds are assumed to be formed between a virtual-carbonyl group in a residue and a downstream virtual-imino group in another residue. Consequently, the period of the formed alpha helix is a noninteger. An improved spatial correlation function has been suggested to quantitatively describe the periodicity of the helical conformation, by which helical period and helical persistent length can be calculated by statistics. The resultant periods are very close to 3.6 residues; the persistent length based upon the improved definition can be larger or smaller than the chain length and reflect the inherent regularity of a chain including one or multiple helical blocks. The simulation outputs agree with the calculation of the Zimm-Bragg theory based upon the associated nucleation parameter and propagation parameter as well.     

Uncovering the Contributions of Charge Regulation to the Stability of Single Alpha Helices**

The single alpha helix (SAH) is a recurring motif in biology. The consensus sequence has a di-block architecture that includes repeats of four consecutive glutamate residues followed by four consecutive lysine residues. Measurements show that the overall helicity of sequences with consensus E₄K₄ repeats is insensitive to a wide range of pH values. Here, we use the recently introduced q-canonical ensemble, which allows us to decouple measurements of charge state and conformation, to explain the observed insensitivity of SAH helicity to pH. We couple the outputs from separate measurements of charge and conformation with atomistic simulations to derive residue-specific quantifications of preferences for being in an alpha helix and for the ionizable residues to be charged vs. uncharged. We find a clear preference for accommodating uncharged Glu residues within internal positions of SAH-forming sequences. The stabilities of alpha helical conformations increase with the number of E₄K₄ repeats and so do the numbers of accessible charge states that are compatible with forming conformations of high helical content. There is conformational buffering whereby charge state heterogeneity buffers against large-scale conformational changes thus making the overall helicity insensitive to large changes in pH. Further, the results clearly argue against a single, rod-like alpha helical conformation being the only or even dominant conformation in the ensembles of so-called SAH sequences.     

Folding pentapeptides into left and right handed alpha helices

Left or right handed alpha helicity can be induced in a pentapeptide (ANGYG) by appending left or right handed helical cycles as chiral templates. This sequence corresponds to a rare left handed helix found in the protein alanine racemase. Circular dichroism spectra reveal that pentapeptide ANGYG has no detectable structure in aq phosphate buffer, that it is an ambidextrous peptide in that it can be directed to fold into either a left handed or right handed alpha helix in water, with greater propensity for the uncommon left handed than the normal right handed conformation. A helix-inducing cyclic peptide at both ends of this peptide was more effective at inducing alpha helicity than a single cyclic peptide at one end. The alpha helical cyclic peptides provide novel tools for folding short peptides into thermodynamically unstable helices in water, and for studying factors that control chirality and helix induction.     

Dynamic Axial-to-Helical Communication Mechanism in Poly[(allenylethynylenephenylene)acetylene]s under External Stimuli

Helix inversion in chiral dynamic helical polymers is usually achieved by conformational changes at the pendant groups induced through external stimuli. Herein, a different mechanism of helix inversion in poly(phenylacetylene)s (PPAs) is presented, based on the activation/deactivation of supramolecular interactions. We prepared poly[(allenylethynylenephenylene)acetylene]s (PAEPAs) in which the pendant groups are conformationally locked chiral allenes. Therefore, their substituents are placed in specific spatial orientations. As a result, the screw sense of a PAEPA is fixed by the allenyl substituent with the optimal size/distance relationship to the backbone. This helical sense command can be surpassed by supramolecular interactions between another substituent on the allene and appropriate external stimuli, such as amines. So, a helix inversion occurs through a novel axial-to-helical communication mechanism, opening a new scenario for taming the helices of chiral dynamic helical polymers.     

Helix-induced asymmetric polymerization

Asymmetric polymerization could be induced by an already formed optically active living prepolymer with one-handed screw sense helix conformation. The usually formed anionic active centre on the prepolymer could be changed to cationic, radical and even of Ziegler-Natta type. These living prepolymers with various kinds of active centre were all effective to induce a consequent asymmetric polymerization of a monomer which may be other than that in the prepolymer, to afford an optically active helical chain with the same screw sense as that of the prepolymer. Eight monomers have been used in the work. Optical rotation, circular dichroism and gelpermeation chromatography have been taken to prove the helix-induced asymmetric polymerization.     

meso Myths: What Drives Assembly of Helical versus meso-[M2L3] Clusters?

Both a triple helix as well as a meso complex are formed by the Ga^III and Al^III complexes with a bis-bidentate bis-hydroxypyridinone ligand H₂L. The two forms are in equilibrium in solution, though formation of the helical structure in the presence of water, which as guest molecule finds sufficient space in the cavity of the helix, is favored (the structure of the helical H₂O⊂[Al₂L₃] complex is shown).     

Amplification of chirality of the majority-rules type in helical supramolecular polymers: the impact of the presence of achiral monomers

We present a theoretical treatment describing the conformational state of helical supramolecular polymers that consist of three types of monomer: right-handed and left-handed chiral monomers and achiral ones. We find that chirality amplification of the majority-rules type, that is, a disproportionately large shift in the helix screw sense due to a small enantiomeric excess, can occur in these polymers. The strength of the chirality amplification depends on the free-energy penalty of a helix reversal along the self-assembled chain and on that of a mismatch between the conformation of a bond and the preferred conformation of the preceding monomer. It turns out that the impact of achiral monomers also depends on these two parameters. For high values of these free energies, the net helicity does not change much from the situation where no achiral material is present. However, if the free-energy penalties are not both large, the impact of the achiral monomers on the conformational state of the aggregates can be quite substantial.     

Doublet Chirality Transfer and Reversible Helical Transition in Poly(3,5‐disubstituted phenylacetylene)s with Pyrene as a Probe Unit†

A novel doublet chirality transfer (DCT) model was demonstrated in cis poly(3,5‐disubstituted phenylacetylene)s, i.e., S‐I , R‐I , and S‐I‐NMe . The chiral message from the stereocenter of alkylamide substituent at 3‐position induced the polyene backbone to take cis‐transoid helical conformation with a predominant screw sense. And in turn the helical backbone acted as a scaffold to orient the pyrene probes, which was linked to phenyl rings through 5‐position, to array in an asymmetric manner. A combinatory analyses of ¹H NMR, Raman, FTIR, UV‐vis absorption, CD, and computer simulation suggested that the main‐chain stereostructure, solvent nature, and intramolecular hydrogen bonds played important and complex roles on DCT. High cis‐structure content and intramolecular hydrogen bonds were beneficial for the realization of DCT. Reversible helix‐helix transition was observed in S‐I by changing the nature of solvents. In DMF, S‐I adopted a relatively contracted helix, where the main chain exhibited strong optical activity, but that of pyrene was weak. In contrast, a relatively stretched helix formed in CHCl₃, in which the optical activity of pyrene was much larger, whereas that of the polyene backbone was the weakest. This helix‐helix transition was attributed to the intramolecular hydrogen bonds, which was confirmed by solution‐state FTIR spectra and computer calculations.     

Solvent- and pH-induced self-assembly of cationic meta-linked poly(phenylene ethynylene): effects of helix formation on amplified fluorescence quenching and Förster resonance energy transfer

We reported here the synthesis and characterization of a novel water-soluble, meta-linked poly(phenylene ethynylene) (m-PPE-NEt(2)Me(+)) featuring quaternized side groups. We studied the solvent-induced self-assembly of m-PPE-NEt(2)Me(+) in MeOH/H(2)O solvent mixtures by using UV-vis absorption and fluorescence spectroscopies. The results showed that the polymer folded into a helical conformation and that the extent of helical folding increased with the volume % water in the solvent. This cationic polymer also exhibited unique pH-induced helix formation, which was attributed to the partial neutralization of quaternized side groups at high pH and the meta-links in the main chain of the polymer. Studies on the fluorescence quenching of m-PPE-NEt(2)Me(+) by anthraquinone-2,6-disulfonate (AQS) and Fe(CN)(6)(4-), two small-molecule anionic quenchers with different typical structures, revealed more efficient quenching of helical conformation by AQS than by Fe(CN)(6)(4-). We proposed that the two quenchers most likely interacted with the polymer helix in two different modes; that was, AQS featuring large planar aromatic ring could intercalate within adjacent π-stacked phenylene ethynylene units in the polymer helix, whereas Fe(CN)(6)(4-) mainly bound to the periphery of polymer helix through ion-pair formation. Finally, the results of FRET from the helical polymer to the fluorescein (C*)-labeled polyanions, ssDNA-C* (ssDNA: single-stranded DNA) and dsDNA-C* (dsDNA: double-stranded DNA) also suggested two different modes of interactions. As compared with the FRET to dsDNA-C*, the FRET to ssDNA-C* was slightly more efficient, which was believed to arise from the additional binding of ssDNA-C* with the polymer via intercalation of its exposed hydrophobic bases into the π stack of adjacent phenylene ethynylene units in the polymer helix.     

Chiral induction in quinoline-derived oligoamide foldamers: assignment of helical handedness and role of steric effects

Chiral groups attached to the end of quinoline-derived oligoamide foldamers give rise to chiral helical induction in solution. Using various chiral groups, diastereomeric excesses ranging from 9% to 83% could be measured by NMR and circular dichroism. Despite these relatively weak values and the fact that diastereomeric helices coexist and interconvert in solution, the right-handed or left-handed helical sense favored by the terminal chiral group could be determined unambiguously using X-ray crystallography. Assignment of chiral induction was performed in an original way using the strong tendency of racemates to cocrystallize, and taking advantage of slow helix inversion rates, which allowed one to establish that the stereomers observed in the crystals do correspond to the major stereomers in solution. The sense of chiral helical induction was rationalized on the basis of sterics. Upon assigning an Rs or Ss chirality to the stereogenic center using a nomenclature where the four substituents are ranked according to decreasing sizes, it is observed that Rs chirality always favors left-handed helicity and Ss chirality favors right-handed helicity (P). X-ray structures shed some light on the role of sterics in the mechanism of chiral induction. The preferred conformation at the stereocenter is apparently one where the bulkiest group should preferentially point away from the helix, the second largest group should be aligned with the helix backbone, and the smallest should point to the helix.     

Supramolecular helical assembly of an achiral cyanine dye in an induced helical amphiphilic poly(phenylacetylene) interior in water

A water-soluble amphiphilic poly(phenylacetylene) bearing the bulky aza-18-crown-6-ether pendants forms a one-handed helix induced by l- or d-amino acids and chiral amino alcohols through specific host-guest interactions in water. We now report that such an induced helical poly(phenylacetylene) with a controlled helix sense can selectively trap an achiral benzoxazole cyanine dye among various structurally similar cyanine dyes within its hydrophobic helical cavity inside the polymer in acidic water, resulting in the formation of supramolecular helical aggregates, which exhibit an induced circular dichroism (ICD) in the cyanine dye chromophore region. The supramolecular chirality induced in the cyanine aggregates could be further memorized when the template helical polymer lost its optical activity and further inverted into the opposite helicity. Thereafter, thermal racemization of the helical aggregates slowly took place.     

Photosensitive chiral polyisocyanates

The dynamic polyisocyanate helix amplifies changes in the conformation of its side groups. Thereby it acts like a fast responding switch for optical properties. Here we show how the photoisomerization of chiral azo side groups can be used to induce large changes of chirooptical properties. These changes can be detected by CD measurements or by ORD measurements far from the absorption region. Large changes of the optical rotation can be induced reversibly in a multicycle process.     

Theoretical study of helix formation in substituted phenylene ethynylene oligomers

Theoretical investigations of the relative stabilities of helical vs extended forms of phenylene ethynylene oligomers established that MMFF molecular mechanics was more useful than AM1 or DFT for calculating helical structures and for estimating relative energies. At the level of MMFF, theory predicts that for o- or m-oligophenylene ethynylenes, helix formation is enthalpically favored for ester and ether-substituted oligomers. In contrast to simple electron-demand predictions, we predict that the position of substituents can make a substantial difference in the tendency to form helices.     

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.     

Following the polyisocyanate helix reversal from dilute solution through the liquid crystal and into the solid state

The absence of a predetermined helical sense in the polyisocyanates causes the formation of helix reversals which enforce a strong cooperativity for the amplification of chiral effects. The helix reversals though also place a limit on this amplification, a limit which would be eliminated by reducing the helix reversal population. Approaching the liquid crystal state of the polyisocyanates in both dilute and concentrated solutions appears to cause the exclusion of the helix reversals which is consistent with theoretical expectations. Since the linear birefringence of the polyisocyanate solid state precludes optical activity measurements associated with the polymer, we have synthesized hydrogen bonding side chain adapted polyisocyanates which appear by DSC and infra-red criteria to form equilibrium molecular composites with copolymers of vinyl phenol and styrene. The optical activity properties of these composites may offer a new way to probe polymer motion in the solid state.     

乙烯基二联苯单体的螺旋选择性自由基聚合

为了深入理解乙烯基二联苯单体自由基聚合过程中的手性传递,进行了手性单体(+)-2-[(S)-异丁氧羰基-5-(4′-己氧基苯基)苯乙烯、非手性单体2-丁氧羰基-5-(4′-己氧基苯基)苯乙烯的均聚反应及它们二者的共聚反应,探讨了聚合温度和溶剂性质对手性单体均聚物旋光活性、手性单体含量对共聚物旋光活性以及聚合反应溶剂的超分子手性对共聚物旋光活性的影响.研究发现,降低聚合温度、采用液晶性反应介质有利于得到旋光度大的聚合物;少量手性单体的引入即可诱导共聚物形成某一方向占优的螺旋构象,比旋光度随手性单体的含量增加呈线性增长;在胆甾相液晶中制备的非手性单体聚合物不具有光学活性.这些结果表明,该类乙烯基二联苯聚合物具有动态螺旋构象,其光学活性主要依赖于主链的立构规整度和侧基不对称原子的手性.