Effects of the alternating backbone configuration on the secondary structure and self-assembly of beta-peptides

Heterochiral homo-oligomers with alternating backbone configurations were constructed by using the different enantiomers of the cis- and trans-2-aminocyclopentanecarboxylic acid (ACPC) monomers. Molecular modeling and the spectroscopic techniques (NMR, ECD, and VCD) unequivocally proved that the alternating heterochiral cis-ACPC sequences form an H10/12 helix, where extra stabilization can be achieved via the cyclic side chains. The ECD and TEM measurements, together with molecular modeling, revealed that the alternating heterochiral trans-ACPC oligomers tend to attain a polar-strand secondary structure in solution, which can self-assemble into nanostructured fibrils. The observations indicate that coverage of all the possible secondary structures (various helix types and strand-mimicking conformations) can be attained with the help of cyclic beta-amino acid diastereomers. A relationship has been established between the backbone chirality pattern and the prevailing secondary structure, which underlines the role of stereochemical control in the beta-peptide secondary structure design and may contribute to future biological applications.     

Photoinduced chirality in azobenzene-containing polymer systems

In this article, we will review the phenomena on circularly-polarized-light (CPL)-induced chirality in polymeric systems with photochromophores in their side-chain or main-chain. In the side-chain polymeric systems, the photoinduced chirality arises from superstructural chirality, i.e., helix structure, via aggregating of achiral azobenzene molecules in side chains. On the other hand, in the main-chain polymeric system, the macroscopically induced chirality can originate from individual chirality of chromophores in their main-chain backbone. The CPL irradiation on polymeric films with photochromophores to produce macroscopic chirality has been realized as potentially useful in the development of optical-switching, optical-storage, and light-driven devices.     

Supramolecular chirality formation of bisazobenzene-substituted polydiacetylene LB films

In order to investigate the exact effect of stereoregular packing of head group in the side chain on the helical structure formation of polydiacetylene backbone, the larger size of bisazobenzene-substituted diacetylene monomer, 4-(4-nitrophenylazo) azobenzene-10, 12-pentacosadiynoate (BNADA) was synthesized successfully. Owing to overcrowded packing of bisazobenzene chromophores, the BNADA Langmuir-Blodgett (LB) films showed macroscopic supramolecular chirality, although BNADA molecules were achiral. Under circularly polarized UV light (CPUL) irradiation, supramolecular helix of bisazobenzene chromophores always maintained, due to the large size and lower photo-isomerization rate of bisazeobenzene chromophores. While for polydiacetylene backbone, the helical direction of the polymer chain should be decided by the competition of the effect of stereoregular packing of bisazobenzene chromophores and the interaction between the CPUL and the diacetylene dimer.     

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.     

Cluster expansion models for flexible‐backbone protein energetics

Protein structure prediction and design often involve discrete modeling of side‐chain conformations on structural templates. Introducing backbone flexibility into such models has proven important in many different applications. Backbone flexibility improves model accuracy and provides access to larger sequence spaces in computational design, although at a cost in complexity and time. Here, we show that the influence of backbone flexibility on protein conformational energetics can be treated implicitly, at the level of sequence, using the technique of cluster expansion. Cluster expansion provides a way to convert structure‐based energies into functions of sequence alone. It leads to dramatic speed‐ups in energy evaluation and provides a convenient functional form for the analysis and optimization of sequence‐structure relationships. We show that it can be applied effectively to flexible‐backbone structural models using four proteins: α‐helical coiled‐coil dimers and trimers, zinc fingers, and Bcl‐x_L/peptide complexes. For each of these, low errors for the sequence‐based models when compared with structure‐based evaluations show that this new way of treating backbone flexibility has considerable promise, particularly for protein design. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2009     

Turn and helical peptide handedness governed exclusively by side-chain chiral centers

We have examined the preferred 3D structure of homopeptides based on an alpha-amino acid lacking the asymmetry at the alpha-carbon but exhibiting chirality in the side chains (at the two beta-carbons). These joint stereochemical properties are remarkably unusual for an alpha-amino acid. To this end, we carried out an experimental investigation by X-ray diffraction and NMR spectrometry. The results point to a well-defined relationship between screw sense of the turn and helix structures formed and side-chain configurations.     

Isosteric Substitutions of Urea to Thiourea and Selenourea in Aliphatic Oligourea Foldamers: Site‐Specific Perturbation of the Helix Geometry

Nearly isosteric oxo to thioxo substitution was employed to interrogate the structure of foldamers with a urea backbone and explore the relationship between helical folding and hydrogen‐bonding interactions. A series of oligomers with urea bonds substituted by thiourea bonds at discrete or all positions in the sequence have been prepared and their folding propensity was studied by using a combination of spectroscopic methods and X‐ray diffraction. The outcome of oxo to thioxo replacements on the helical folding was found to depend on whether central or terminal ureas were modified. The canonical helix geometry was not affected upon insertion of thioureas close to the negative end of the helix dipole, whereas thioureas close to the positive pole were found to increase the terminal flexibility and cause helix fraying. Perturbation was amplified when a selenourea was incorporated instead, leading to a structure that is only partly folded.     

Synthesis of Self‐Threading Bithiophenes and their Structure–Property Relationships Regarding Cyclic Side‐Chains with Atomic Precision

We have recently reported a self‐threading polythiophene as a new family of insulated molecular wires. Herein, we focused on the structure–property relationships of the unique three‐dimensional architecture of the monomer. We have synthesized nine self‐threading bithiophene monomers that have cyclic side‐chains of different size and flexibility: i.e., 21‐, 22‐, 23‐, 24‐, 26‐, and 30‐membered rings composed of paraffinic, olefinic, or alkynic chains. To investigate their structure–property relationships, ¹H NMR spectroscopy, UV absorption, and fluorescence spectroscopy measurements were conducted. We found that cyclic side‐chains define the movable range of the dihedral angle of the bithiophene backbone, thereby affecting its photophysical properties. Therefore, the ability to design a structure with atomic precision as described herein would lead to the fine‐tuning of the electronic properties of insulated molecular wires.     

Improving the strategy and performance of molecularly imprinted polymers using cross-linking functional monomers

A new strategy for monomer design has been investigated that combines interactive monomer functionality with a cross-linking format, giving as a result noncovalent molecularly imprinted polymers (MIPs) with improved performance. This strategy was explored under the premise that more functionality could be introduced without suffering performance losses due to reduced cross-linking. While this proved to be correct, equally important contributions to selectivity enhancement at the molecular level by conformation control and diastereomeric complexation were also discovered. Monomers derived from l-serine and l-aspartic acid were synthesized and used to prepare MIPs, with the best performance obtained for the MIP formulated with the serine-based cross-linker (N,O-bis-methacryloyl l-serine, 3), versus the aspartic-acid-based cross-linkers and the traditional methacrylic acid/ethylene glycol dimethacrylate (MAA/EGDMA) formulation. Quantitative structure-selectivity relationship (QSSR) studies revealed that the improved performance of 3 was due to three key factors: (1) the cross-linking nature of this monomer; (2) control of conformational flexibility; (3) a strong influence of monomer chirality on enantioselectivity in MIPs.     

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.     

Mechanism of helix induction on a stereoregular Poly((4-carboxyphenyl)acetylene) with chiral amines and memory of the macromolecular helicity assisted by interaction with achiral amines

Cis-transoidal poly((4-carboxyphenyl)acetylene) (poly-1) is an optically inactive polymer but forms an induced one-handed helical structure upon complexation with optically active amines such as (R)-(1-(1-naphthyl)ethyl)amine ((R)-2) in DMSO. The complexes show a characteristic induced circular dichroism (ICD) in the UV-visible region of the polymer backbone. Moreover, the macromolecular helicity of poly-1 induced by (R)-2 can be "memorized" even after complete replacement of (R)-2 by various achiral amines. We now report fully detailed studies on the mechanism of the helicity induction and memory of the helical chirality of poly-1 by means of UV-visible, CD, and infrared spectroscopies. We have found that a one-handed helix is cooperatively induced on poly-1 upon the ion pair formation of the carboxy groups of poly-1 with optically active amines and that the bulkiness of the chiral amines plays a crucial role for inducing an excess of a single-handed helix. On the other hand, the free ion formation was found to be essential for the macromolecular helicity memory of poly-1 after the replacement of the chiral amine by achiral amines, since the intramolecular electrostatic repulsion between the neighboring carboxylate ions of poly-1 significantly contributes to reduce the atropisomerization process of poly-1. On the basis of the mechanism of helicity induction and the memory of the helical chirality drawn from the present studies, we succeeded in creating an almost perfect memory of the induced macromolecular helicity of poly-1 with (R)-2 by using 2-aminoethanol as an achiral chaperoning molecule to assist in maintaining the memory of helical chirality.     

Metal-Coordination-Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules

The development of foldamer-based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine-pyridine-pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine-pyridine-pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.     

Potential‐Driven Chirality Manifestations and Impressive Enantioselectivity by Inherently Chiral Electroactive Organic Films

The typical design of chiral electroactive materials involves attaching chiral pendants to an electroactive polyconjugated backbone and generally results in modest chirality manifestations. Discussed herein are electroactive chiral poly‐heterocycles, where chirality is not external to the electroactive backbone but inherent to it, and results from a torsion generated by the periodic presence of atropisomeric, conjugatively active biheteroaromatic scaffolds, (3,3′‐bithianaphthene). As the stereogenic element coincides with the electroactive one, films of impressive chiroptical activity and outstanding enantiodiscrimination properties are obtained. Moreover, chirality manifestations can be finely and reversibly tuned by the electric potential, as progressive injection of holes forces the two thianaphthene rings to co‐planarize to favor delocalization. Such deformations, revealed by CD spectroelectrochemistry, are elastic and reversible, thus suggesting a breathing system.     

柔性间隔基对于香豆素取代二乙炔LB膜聚合及手性形成的影响

设计合成了2种香豆素取代二乙炔单体,7-(10,12-二十三双炔酰氧基)-香豆素(CODA)和7-(10,12-二十三双炔酰氧乙氧基)-香豆素(CO2DA),研究了柔性间隔基对香豆素取代二乙炔单体在气-液界面的组装、单体LB膜的聚合以及聚二乙炔主链螺旋结构形成的影响.利用Langmui-Blodgett(LB)技术,以纯水为亚相,膜压在35 mN/m时沉积制备了香豆素取代二乙炔单体LB膜.尽管CODA是非手性的,但其LB膜均表现出明显的宏观手性信号.这是由于在压缩过程中香豆素基团间强烈的π-π堆积,形成了螺旋排列,显示出超分子手性.而CO2DA LB膜无明显CD信号.经254 nm紫外光辐照,CODA LB膜聚合成蓝相,聚二乙炔主链表现出明显的宏观手性.而CO2DA LB膜聚合后无明显的CD信号.薄膜中香豆素功能基团的不规则排列不利于二乙炔单体的固态聚合以及聚二乙炔主链螺旋结构的形成.     

Chirality in Dynamic Supramolecular Nanotubes Induced by a Chiral Solvent

Amplification of chirality has been reported in polymeric systems. It has also been shown that related effects can occur in polymer‐like dynamic supramolecular aggregates, if a subtle balance between noncovalent interactions allows the coupling between a chiral information and a cooperative aggregation process. In this context, we report a strong majority‐rules effect in the formation of chiral dynamic nanotubes from chiral bisurea monomers. Furthermore, similar helical nanotubes (with the same circular dichroism signature) can be obtained from racemic monomers in a chiral solvent. Competition experiments reveal the relative strength of the helical bias induced by the chiral monomer or by the chiral solvent. The nanotube handedness is imposed by the monomer chirality, whatever the solvent chirality. However, the chirality of the solvent has a significant effect on the degree of chiral induction.     

Metal‐Coordination‐Assisted Folding and Guest Binding in Helical Aromatic Oligoamide Molecular Capsules

The development of foldamer‐based receptors is driven by the design of monomers with specific properties. Herein, we introduce a pyridazine‐pyridine‐pyridazine diacid monomer and its incorporation into helical aromatic oligoamide foldamer containers. This monomer codes for a wide helix diameter and can sequester metal ions on the inner wall of the helix cavity. Crystallographic studies and NMR titrations show that part of the metal coordination sphere remains available and may then promote the binding of a guest within the cavity. In addition to metal coordination, binding of the guest is assisted by cooperative interactions with the helix host, thereby resulting in significant enhancements depending on the foldamer sequence, and in slow guest capture and release on the NMR time scale. In the absence of metal ions, the pyridazine‐pyridine‐pyridazine monomer promotes an extended conformation of the foldamer that results in aggregation, including the formation of an intertwined duplex.     

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.     

Discrimination of the enantiomers of biphenylic derivatives in micellar aggregates formed by chiral amidic surfactants

The chirality of micellar aggregates formed by surfactants derived from l-proline was investigated by using two chiral biphenylic derivatives as probes of chirality. The investigation carried out by ¹H NMR, circular dichroism, and HPLC on chiral phase demonstrates that chiral recognition may occur in sites of the aggregates far from the head-group stereogenic centers and it is due to interaction with a whole region of the aggregate rather than with a single monomer in the aggregate. Subtle changes of the structure of the monomer influence the aggregation properties of the surfactants and its expression of chirality.     

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

Oligomeric N-substituted glycines or "peptoids" with alpha-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 pi clouds of aromatic rings in the side chains. Interestingly, these peptoid helices exhibit intense circular dichroism (CD) spectra that closely resemble those of peptide alpha-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.     

Modeling loop backbone flexibility in receptor‐ligand docking simulations

The relevance of receptor conformational change during ligand binding is well documented for many pharmaceutically relevant receptors, but is still not fully accounted for in in silico docking methods. While there has been significant progress in treatment of receptor side chain flexibility sampling of backbone flexibility remains challenging because the conformational space expands dramatically and the scoring function must balance protein–protein and protein–ligand contributions. Here, we investigate an efficient multistage backbone reconstruction algorithm for large loop regions in the receptor and demonstrate that treatment of backbone receptor flexibility significantly improves binding mode prediction starting from apo structures and in cross docking simulations. For three different kinase receptors in which large flexible loops reconstruct upon ligand binding, we demonstrate that treatment of backbone flexibility results in accurate models of the complexes in simulations starting from the apo structure. At the example of the DFG‐motif in the p38 kinase, we also show how loop reconstruction can be used to model allosteric binding. Our approach thus paves the way to treat the complex process of receptor reconstruction upon ligand binding in docking simulations and may help to design new ligands with high specificity by exploitation of allosteric mechanisms. © 2012 Wiley Periodicals, Inc.