Left-handed Helix Research Articles

Protein-based 2D Nanoarchitectures Constructed by Heterochiral π-Stacking Dimerization of Helical Foldamers.

In this study, we focus on the designability and controllability of the interaction interface between secondary structures, and discover an important interface interaction between helical secondary structures by non-covalent synthesis along the helical axis. The formation of discrete heterochiral dimers consisting of left-handed helix and right-handed helix not only helps to discover nonclassical supramolecular chirality phenomena, but also enables controllable protein assembly. Highly ordered nanostructures were thus constructed using p-stacking dimerization of helical foldamers to control tetrameric avidin proteins. The designable and modifiable primitives of artificial folded molecules enable the modification of secondary structure interfaces through non-covalent interactions, leading to the generation of unique structures and functions. These findings are of fundamental importance to the understanding of the precise assembly process of helical foldamers and can provide insights to facilitate the rational design of abiotic protein-like tertiary structures and further functionalization.

Engineering circularly polarized luminescence through symmetry manipulation in achiral tetraphenylpyrazine structures

Symmetry breaking, a critical phenomenon in both natural and artificial systems, is pivotal in constructing chiral structures from achiral building units. This study focuses on the achiral molecule 8,8',8'',8'''-((pyrazine-2,3,5,6-tetrayltetrakis(benzene-4,1-iyl))tetrakis(oxy))tetrakis (octan-1-ol) (TPP-C8OH), an aggregation-induced emission (AIE) molecule, to explore its symmetry breaking behavior in supramolecular assembly. By analyzing TPP-C8OH in various solvents‒both non-chiral and chiral‒ we found that chiral solvents significantly enhance the molecule’s symmetry breaking and chiroptical properties. Specially, alcohol solvents, particularly dodecyl alcohol, facilitated the formation of helical structures with both left-handed (M) and right-handed (P) helices within single twisted nanoribbons. This observation contrasts with previously reported symmetry breaking phenomena in assembly systems. Chiral solvents induced assemblies with distinct helical orientations, resulting in notable circularly polarized luminescence (CPL) and circular dichroism (CD) signals. This study elucidates the impact of solvent choice on symmetry breaking and chiral assembly, offering insights into the design of advanced chiral materials with tailored self-assembly processes.

Heterochiral π-Stacking Dimerization of Helical Secondary Structures with Emerging Supramolecular Chirality.

A specific interface mode type was observed between helical secondary structures, in which a left-handed (M) helix binds specifically to a right-handed (P) helix along the helical axis, leading to the formation of discrete heterochiral helical dimers. Moreover, a concealed supramolecular chirality within the meso-supramolecular dimers was unexpectedly discovered by chiral induction, and was further underpinned by covalent meso-helix structures.

Chiral Ca–Mn-frameworks with double helical chains and one-dimensional channels constructed from enantiomorphous lactate synthons

Under solvothermal synthetic condition, lactate derivatives (R)-5-(1- carboxyethoxy)isophthalic acid ((R)-H3CIA) and (S)-5-(1-carboxyethoxy)isophthalic acid ((S)–H3CIA) assembled with Ca(Ⅱ) and Mn(Ⅱ) ions to obtain enantiomers {[MnCa0.5((R)-CIA)(H2O)]·((CH3)2NH2CH3CO2)0.5(H2O)}n (HU21-R) and {[MnCa0.5((S)-CIA)(H2O)]·((CH3)2NH2CH3CO2)0.5(H2O)}n (HU21–S), respectively. Complexes HU21-R and HU21–S belong to orthorhombic crystal system with chiral space group I212121. Single crystal X-ray diffraction analysis revealed that all oxygen atoms of synthons (R)-CIA3- and (S)-CIA3- participated in the coordination with metal ions. Thus, semi-rigid (R)-CIA3- and (S)-CIA3- anions become rigid linkers in HU21-R and HU21–S. Fragments of (R)-CIA3- anion are connected by Ca(Ⅱ) ions to build right-handed double helical chains in HU21-R, while the enantiomeric left-handed double helixes are constructed by (S)-CIA3- fragments and Ca(Ⅱ) ions in HU21–S. Additionally, Mn(Ⅱ) centers and CIA3− anions resulted in a rare 4,4,4-connected net with point symbol of (42.62.82)3(42.64). Ca(Ⅱ) ions were further filed into Mn-CIA-framework to form a three dimensional structure with one dimensional channel. Moreover, magnetic test indicates that the framework has a canted antiferromagnetic behavior.

Unveiling the anion-specific effect induced structure and behavior variations on a single chitin chain

Ion-specific effects have a profound impact on the macroscopic properties of polysaccharides such as the aggregation and solubility in solutions. However, the underlying molecular mechanisms still require exploration. In this study, we investigated the influence of anions on the structure and behavior of chitin via a combination of single-molecule techniques and macroscopic characterizations. Our findings reveal that the hydration of anions functions as bridging center, leading to the formation of water-ion-water bridges between chitin side groups. Remarkably, this structure exhibits a binding affinity to chitin following the Hofmeister series with the order of F− < Cl− < Br− < I−, resulting in an escalating of left-handed helix order of chitin. Subsequent experiments indicate that the bridging structure affects the size of chitin aggregates in the similar manner, implying the impact of anions on the structure and behavior of chitin across length scales. These results provide valuable insights into the understanding of ion-specific effects on polysaccharides and its applications in food science where high salt environments are involved.

Formation of left-handed helices by C2'-fluorinated nucleic acids under physiological salt conditions.

Recent findings in cell biology have rekindled interest in Z-DNA, the left-handed helical form of DNA. We report here that two minimally modified nucleosides, 2'F-araC and 2'F-riboG, induce the formation of the Z-form under low ionic strength. We show that oligomers entirely made of these two nucleosides exclusively produce left-handed duplexes that bind to the Zα domain of ADAR1. The effect of the two nucleotides is so dramatic that Z-form duplexes are the only species observed in 10 mM sodium phosphate buffer and neutral pH, and no B-form is observed at any temperature. Hence, in contrast to other studies reporting formation of Z/B-form equilibria by a preference for purine glycosidic angles in syn, our NMR and computational work revealed that sequential 2'F…H2N and intramolecular 3'H…N3' interactions stabilize the left-handed helix. The equilibriumbetween B- and Z- forms is slow in the 19F NMR time scale (≥ms), and each conformation exhibited unprecedented chemical shift differences in the 19F signals. This observation led to a reliable estimation of the relative population of B and Z species and enabled us to monitor B-Z transitions under different conditions. The unique features of 2'F-modified DNA should thus be a valuable addition to existing techniques for specific detection of new Z-binding proteins and ligands.

Neighbor effect on conformational spaces of alanine residue in azapeptides

The conformational properties of Alanine (Ala) residue have been investigated to understand protein folding and develop force fields. In this work, we examined the neighbor effect on the conformational spaces of Ala residue using model azapeptides, Ac-Ala-azaGly-NHMe (3, AaG), and Ac-azaGly-Ala-NHMe (4, aGA1). Ramachandran energy maps were generated by scanning (φ, ψ) dihedral angles of the Ala residues in models with the fixed dihedral angles (φ = ±90°, ψ = ±0° or ±180°) of azaGly residue using LCgau-BOP and LCgau-BOP + LRD functionals in the gas and water phases. The integral-equation-formalism polarizable continuum model (IEF-PCM) and a solvation model density (SMD) were employed to mimic the solvation effect. The most favorable conformation of Ala residue in azapeptide models is found as the polyproline II (βP), inverse γ-turn (γ′), β-sheet (βS), right-handed helix (αR), or left-handed helix (αL) depending on the conformation of neighbor azaGly residue in isolated form. Solvation methods exhibit that the Ala residue favors the βP, δR, and αR conformations regardless of its position in azapeptides 3 and 4 in water. Azapeptide 5, Ac-azaGly-Ala-NH2 (aGA2), was synthesized to evaluate the theoretical results. The X-ray structure showed that azaGly residue adopts the polyproline II (βP) and Ala residue adopts the right-handed helical (αR) structure in aGA2. The conformational preferences of aGA2 and the dimer structure of aGA2 based on the X-ray structure were examined to assess the performance of DFT functionals. In addition, the local minima of azapeptide 6, Ac-Phe-azaGly-NH2 (FaG), were compared with the previous experimental results. SMD/LCgau-BOP + LRD methods agreed well with the reported experimental results. The results suggest the importance of weak dispersion interactions, neighbor effect, and solvent influence in the conformational preferences of Ala residue in model azapeptides.

Dynamic individual pitch control for wake mitigation: Why does the helix handedness in the wake matter?

Wind farm flow control aims at mitigating wake effects in order to maximize power production in wind farms. This work mostly focuses on the Helix strategy, which relies on individual pitch control to radially offset the application point of the thrust force from the rotor center and to dynamically change its azimuthal position. Previous studies have shown that power gains for a downstream turbine are higher for a counter-clockwise (CCW) rotation of the application point than for a clockwise (CW) one. In the CCW case, the wake develops as a right-handed helix, while in the CW case, a left-handed helix is observed. Using Large Eddy Simulations, this paper shows that the helix handedness in the wake matters due to its interaction with the wake swirl. Results of the CCW and CW helix first highlight the formation of streamwise vorticity in the near wake, which is transformed into strong coherent vortices in the far wake. Those vortex structures, to some extent similar to the counter-rotating vortex pair in the wake of yawed wind turbines, are responsible for (i) displacing the wake thanks to their induced velocities and (ii) deforming the shape of the wake.

Surprising Wilkins’ error (Nature 1953, 172: 755–762)

The Nobel Prize in Physiology or Medicine 1962 was awarded jointly to Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins “for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”. Building the scale atomic-molecular models and applying strong inference Watson and Crick (1953a,b) presented convincing evidences for the following features of the spatial structure of the DNA molecule: (i) this structure has two helical chains each coiled round the same axis; (ii) both chains follow right-handed helices; (iii) the sequences of the atoms in the two chains run in opposite directions; (iv) the two chains are held together by hydrogen-bonded purine and pyrimidine bases; (v) the planes of the bases are perpendicular to the fibre axis; (vi) only specific pairs of bases can bond together: adenine (purine) with thymine (pyrimidine), and guanine (purine) with cytosine (pyrimidine). X-ray evidence obtained at the same time by Wilkins et al. (1953a,b), and Franklin et al. (1953a,b) gave qualitative support to this structure and was incompatible with all previously proposed structures. Wilkins et al. (1953b) built molecular models of the type described by Watson and Crick (1953a) and adjusted them to conform with their experimental data. However, it appeared that the paper by Wilkins et al. (1953b) contains a curious and inexplicable error. Namely, in their Figure 3 DNA is schematically drawn as a left-handed helix, which, as Crick and Watson (1954) explained, is stereochemically impossible and must be right-handed. The fact stated here was mysteriously not noticed before and, fortunately, had no detrimental effect on the development of science.

Osteogenesis imperfecta type 10 and the cellular scaffolds underlying common immunological diseases.

Osteogenesis imperfecta type 10 (OI10) is caused by loss of function codon variants in the gene SERPINH1 that encodes heat shock protein 47 (HSP47), rather than in a gene specifying bone formation. The HSP47 variants disrupt the folding of both collagen and the endonuclease IRE1α (inositol-requiring enzyme 1α) that splices X-Box Binding Protein 1 (XBP1) mRNA. Besides impairing bone development, variants likely affect osteoclast differentiation. Three distinct biochemical scaffold play key roles in the differentiation and regulated cell death of osteoclasts. These scaffolds consist of non-templated protein modifications, ordered lipid arrays, and protein filaments. The scaffold components are specified genetically, but assemble in response to extracellular perturbagens, pathogens, and left-handed Z-RNA helices encoded genomically by flipons. The outcomes depend on interactions between RIPK1, RIPK3, TRIF, and ZBP1 through short interaction motifs called RHIMs. The causal HSP47 nonsynonymous substitutions occur in a novel variant leucine repeat region (vLRR) that are distantly related to RHIMs. Other vLRR protein variants are causal for a variety of different mendelian diseases. The same scaffolds that drive mendelian pathology are associated with many other complex disease outcomes. Their assembly is triggered dynamically by flipons and other context-specific switches rather than by causal, mendelian, codon variants.

A Unique Temperature-Induced Reverse Supramolecular Chirality-Assisted Gel-to-Gel Transition.

Supramolecular hydrogels typically undergo a gel-to-sol transition with heat, as intermolecular interactions within the gel weaken. Although gel-to-gel transitions during heating are rare, they may occur due to minor rearrangements caused by thermal forces in the supramolecular self-assembled structure. Here, an unprecedented temperature-induced gel-to-gel transition assisted by supramolecular chiral inversion in a hydrogel system is presented. The transition results from a left-handed M-type helix to a right-handed P-type helix, attributed to the π-system-conjugated amino acid, l-Tyrosine (Fm- l-Tyr). Upon solvent dilution, Fm-l-Tyr induces translucent hydrogel formed by entangled fibers with a kinetically stable left-handed M-type supramolecular helix. At 70 °C, hydrogel transforms into an opaque gel with a reverse supramolecular chirality yielding a thermodynamically stable right-handed P-type helix. Supramolecular chiral inversion is substantiated by two chiroptical methods. This unique gel-to-gel transition, accompanied by chiral inversion, is anticipated to attract attention, especially for applications sensitive to chirality.

Why Are Left-Handed G-Quadruplexes Scarce?

G-quadruplexes (G4s) are nucleic acid structures crucial for the regulation of gene expression and genome maintenance. While they hold promise as nanodevice components, achieving desired G4 folds requires understanding the interplay between stability and structural properties, like helicity. Although right-handed G4 structures dominate the experimental data, the molecular basis for this preference over left-handed helicity is unclear. To address this, we employ all-atom molecular dynamics simulations and quantum chemical methods. Our results reveal that right-handed G4s exhibit greater thermodynamic and kinetic stability as a result of favorable sugar-phosphate backbone conformations in guanine tracts. Moreover, while hydrogen-bonding patterns influence helicity-specific G4 loop conformations, they minimally affect stability differences. We also elucidate the strong correlation between helicity and the strand progression direction, essential for G4 structures. These findings deepen our understanding of G4s, providing molecular-level insights into their structural and energetic preferences, which could inform the design of novel nanodevices.

ZP2 cleavage blocks polyspermy by modulating the architecture of the egg coat

Following the fertilization of an egg by a single sperm, the egg coat or zona pellucida (ZP) hardens and polyspermy is irreversibly blocked. These events are associated with the cleavage of the N-terminal region (NTR) of glycoprotein ZP2, a major subunit of ZP filaments. ZP2 processing is thought to inactivate sperm binding to the ZP, but its molecular consequences and connection with ZP hardening are unknown. Biochemical and structural studies show that cleavage of ZP2 triggers its oligomerization. Moreover, the structure of a native vertebrate egg coat filament, combined with AlphaFold predictions of human ZP polymers, reveals that two protofilaments consisting of type I (ZP3) and type II (ZP1/ZP2/ZP4) components interlock into a left-handed double helix from which the NTRs of type II subunits protrude. Together, these data suggest that oligomerization of cleaved ZP2 NTRs extensively cross-links ZP filaments, rigidifying the egg coat and making it physically impenetrable to sperm.

The Binding Properties of Antibodies to Z-DNA in the Sera of Normal Healthy Subjects.

Antibodies to DNA are a diverse set of antibodies that bind sites on DNA, a polymeric macromolecule that displays various conformations. In a previous study, we showed that sera of normal healthy subjects (NHS) contain IgG antibodies to Z-DNA, a left-handed helix with a zig-zig backbone. Recent studies have demonstrated the presence of Z-DNA in bacterial biofilms, suggesting a source of this conformation to induce responses. To characterize further antibodies to Z-DNA, we used an ELISA assay with brominated poly(dGdC) as a source of Z-DNA and determined the isotype of these antibodies and their binding properties. Results of these studies indicate that NHS sera contain IgM and IgA as well as IgG anti-Z-DNA antibodies. As shown by the effects of ionic strength in association and dissociation assays, the anti-Z-DNA antibodies bind primarily by electrostatic interactions; this type of binding differs from that of induced anti-Z-DNA antibodies from immunized animals which bind by non-ionic interactions. Furthermore, urea caused dissociation of NHS anti-Z-DNA at molar concentrations much lower than those for the induced antibodies. These studies also showed IgA anti-Z-DNA antibodies in fecal water. Together, these studies demonstrate that antibodies to Z-DNA occur commonly in normal immunity and may arise as a response to Z-DNA of bacterial origin.

The Solid-Phase Transition of Carbapenem CS-023 Polymorphs and the Change in Helicity Observed in the Transition

Anti-solvent crystallization of carbapenem CS-023 was performed at 25 °C. The following results were obtained: (1) A solvate crystal, Form A (5/2 Ethanol·1/2 H2O), was recovered from 80 v/v% ethanol solution; (2) Form A transformed to Form H (4H2O) through solid-phase transition through the solvate-free polymorph, Form A-2, and Form A also transformed into Form C (1Ethanol·3H2O) through solvent-mediated transformation. In the present study, we found that Form C also transforms to Form H through the solid-phase transition through the solvate-free polymorph Form C-2. The three polymorphs, Forms A, H, and C, were composed of helical chain structures. However, there was an incomprehensible affair in the solid-phase transition among the three polymorphs. Namely, Form A comprised a left-handed helix. On the other hand, Form C’s and Form H’s helix chains were in a left- and right-handed helix complex, respectively. The solid-phase transition of Form A into Form H suggested a switch in helicity in the solid. We attempted to explain the helicity change in the solid-phase transition. As a result, we suggest that the over-absorption of water by Form A-2 at high humidity plays a vital role in the helicity change.

Helicity Control of Circularly Polarized Luminescence from Aromatic Conjugated Copolymers and Their Mixture Using Reversibly Photoinvertible Chiral Liquid Crystals.

We synthesized cyclic chiral compounds [(R)/(S)-D2s] by linking a photoresponsive bisbenzothienylethene (BTE) moiety with an axially chiral binaphthyl moiety. Chiral nematic liquid crystals (N*-LCs) were prepared by adding chiral compounds as dopants to host N-LCs. These N*-LCs exhibited reversible chirality inversion upon photoisomerization between the open and closed forms of the BTE moiety. Here, the mechanism underlying chirality inversion in photoresponsive N*-LCs was investigated by comparing the helical twisting powers (HTPs) of (R)-D2s with those of analogous compounds. It was found that the helical inversion of N*-LCs containing (R)-D2s is governed by a delicate balance between two types of opposite helicity, i.e., the right-handed helicity of the inherently chiral binaphthyl moiety and the left-handed helicity of the BTE moiety bearing intramolecularly induced chirality. Namely, (R)-D2s induced chirality of the BTE moiety, which is attributed to intramolecular chirality transfer from the axially chiral binaphthyl moiety to the BTE moiety. Thus, (R)-D2s are chiral compounds with double chirality consisting of an intrinsically chiral moiety and an intramolecularly induced chiral moiety. Photocontrol of the helical senses and reversible photoinversion of the N*-LCs are achieved by utilizing UV and visible light irradiation and the steric effects of the substituents at the binaphthyl rings in (R)-D2s. In addition, photocontrol of the induced circularly polarized luminescence (CPL) was achieved using the photoinvertible N*-LC. The achiral aromatic conjugated copolymers that exhibited red, green, and blue fluorescence were dissolved and mixed in the present N*-LC, and they exhibited left- and right-handed white CPL with large dissymmetry factors (|glum|) ranging from 0.2 to 1.0. The CPLs were reversibly photoswitched due to photoisomerization between the open and PSS forms of the chiral compounds through UV and visible light irradiation.

Helical polyisocyanide-based macroporous organic catalysts for asymmetric Michael addition with high efficiency and stereoselectivity.

Porous materials have attracted interest due to their high specific surface area and rich functionality. Immobilizing organocatalysts onto porous polymers not only boosts enantioselectivity but also improves the reaction rates. In this work, a series of porous polymers C-poly-3ms with rigid polyisocyanide-carrying secondary amine pendants as building blocks were successfully prepared. And the pore size and optical activity of C-poly-3ms can be controlled by the length of the polyisocyanide blocks due to their rigid and helical backbone. C-poly-3150 demonstrated a preferred left-handed helix with a θ 364 value of -8.21 × 103. The pore size and S BET of C-poly-3150 were 17.52 nm and 7.98 m2 g-1, respectively. The porous C-poly-3150 catalyzes the asymmetric Michael addition reaction efficiently and generates the target products in satisfactory yield and excellent enantioselectivity. For 6ab, an enantiomeric excess (ee) and a diastereomeric ratio (dr) up to 99% and 99/1 could be achieved, respectively. The recovered catalyst can be recycled at least 6 times in the asymmetric Michael addition reaction while maintaining activity and stereoselectivity.

Structural Colors from Amyloid-Based Liquid Crystals.

The helical periodicity and layered structure in cholesteric liquid crystals (CLCs) may be tuned to generate structural color according to the Bragg's law of diffraction. A wide range of natural-based materials such as condensed DNA, collagen, chitin, cellulose, and chiral biopolymers exhibit cholesteric phases with left-handed helixes and ensued structural colors. Here, the possibility of using amyloid CLCs is reported to prepare films with iridescent color reflection and opposite handedness. Right-handed CLCs assembled by left-handed amyloid fibrils are dried into layered structures with variable pitch controlled by the addition of glucose. Circularly polarized light with the same handedness of amyloid CLCs helix is reflected in the Bragg regime. Varying the drying speed leads to the switching between films with a rainbow-like color gradient and large area uniform color. It is confirmed that the origin of the colors derives from the layered structures of the amyloid CLCs, given the negligeable birefringence of the films, calculated from optical rotatory dispersion. These findings provide a facile approach to constructing biosourced cholesteric materials and introduce an original class of proteinaceous materials for the generation of structural colors from right-handed circularly polarized light.

The anti-cancer drug candidate CBL0137 induced necroptosis via forming left-handed Z-DNA and its binding protein ZBP1 in liver cells

CBL0137, a promising small molecular anti-cancer drug candidate, has been found to effectively induce apoptosis via activating p53 and suppressing nuclear factor-kappa B (NF-κB). However, it is still not clear whether CBL0137 can induce necroptosis in liver cancer; and if so, what is the underlying molecular mechanism. Here we found that CBL0137 could significantly induce left-handed double helix structure Z-DNA formation in HepG2 cells as shown by Z-DNA specific antibody assay, which was further confirmed by observing the expression of Z-DNA binding protein 1 (ZBP1) and adenosine deaminase acting on RNA 1 (ADAR1). Interestingly, we found that caspase inhibition significantly promoted CBL0137-induced necroptosis, which was further supported with the increase of the late apoptosis and necrosis assessed by the flow cytometry. Furthermore, we found that CBL0137 can also induce the expression of the three necroptosis-related proteins: receptor interacting serine/threonine kinase 1 (RIPK1), receptor interacting serine/threonine kinase 3 (RIPK3), and mixed lineage kinase domain-like (MLKL). Taken together, it was assumed that CBL0137-indued necroptosis in liver cells was due to induction of Z-DNA and ZBP1, which activated RIPK1/RIPK3/MLKL pathway. This represents the first report on the induction of the Z-DNA-mediated necroptosis by CBL0137 in the liver cancer cells, which should provide new perspectives for CBL0137 treatment of liver cancer.

Making Sense of Helices: Right and Wrong Models in Science and Art

Helices are ubiquitous in art and nature. Independent of their pitch and sense of rotation (handedness), helices in sculpture, painting, architecture, scientific illustrations, conference announcements, logos, and advertising are eye-catching and aesthetically pleasing. Helices can turn either clockwise (right-handed helix) or anti-clockwise (left-handed helix). The [Formula: see text]-helix formed by l-amino acids and the double helices formed by [Formula: see text]-d-2′-deoxyribonucleic acid (A- and B-form DNA) and [Formula: see text]-d-ribonucleic acid (A-form RNA) are all right-handed. Artistic license provides the freedom to create helices of any shape and sense; indeed, many helical sculptures do not follow the natural convention observed in proteins and DNA. What is more surprising, given that models of the [Formula: see text]-helix and the DNA double helix were published over 70 years ago, is how common left-handed DNA double helices are in the context of scientific papers and books as well as in popular science writing and reporting. In all cases except for left-handed Z-DNA, the use of left-handed helices in scientific illustrations or models is incorrect. Here, we revisit the helix types adopted by peptides, DNA, and RNA, and review examples of right and wrong helical models in science, art, and elsewhere.