CH-π Interactions Research Articles

Diastereoselective Supramolecular Encapsulation and Chirality Transfer Between Cholesteryl Binaphthyl Conjugates and Polyaromatic Hydrocarbon.

Diastereoselective effect plays an important role in the synthesis of chiral complexes and macrocyclic compounds, while its function in selective coassembly and chirality transfer has yet to be unveiled. In this work, two pairs of diastereomers containing R/S- binaphthyl and homochiral cholesteryl domains are synthesized, which provide multiple sites to encapsulate polyaromatic hydrocarbon through π-π and CH-π interactions. X-ray structures and computational studies suggest the binaphthol derivatives feature CH-π folding into butterfly-like open geometry, while binaphthylenediamine derivatives adopt closed geometry supported by van der Waals between cholesteryl domains. Driven by solvophobic forces, the building units self-assemble into vesicles and nanofibers in the aqueous and methanol phases, respectively. Binaphthol derivatives selectively encapsulate pyrene by naphthalene domains in the vesicle phase, while binaphthylenediamine derivatives encapsulate pyrene by cholesteryl domains in the nanofiber phase. Density functional theory-based calculations and circular dichroism spectra evidence the closed geometry of binaphthylenediamine derivatives facilitates a clamp-type host to increase the affinity toward pyrene in spite of the strong solvation competition. This work unveils the diastereoselectivity in the chiral coassembly, deepening the understanding of the precise synthesis of functional chiroptical complexes.

Favored CH-π interaction between enzymatically modified high amylose starch and resveratrol improves digestion resistance

Starch-stilbene polyphenol complexes, a novel form of resistant starch (RS), have received considerable attention due to their potential health benefits. To enhance the functionality of this type of complex, we examined the interactions between resveratrol (RA) and high-amylose starch with different molecular weights, achieved through enzymatic modification followed by high-pressure homogenization (HPH). We examined how these interactions affect the digestibility and ordered structures of the complexes. Our findings reveal that, notwithstanding the inhibition of double helix and B-type crystalline structure formation, RA-starch complexation markedly boosted single helix content, V-type crystalline structure formation, and aggregate structure density. These effects contributed notably to increased RS content. Interestingly, the formation of the V6-type crystalline structure within the complexes was primarily facilitated by the CH-π interaction between the aromatic rings of RA and the C–H of starch, rather than conventional hydrogen bonding and electrostatic forces. The strength of the CH-π interaction increased with higher amylose content and lower molecular weight of the starch, achievable through a 12-h pullulanase hydrolysis followed by a 2-h α-amylase hydrolysis. The resulting HPH-Pα2-RA complexes exhibited remarkable levels of the V-type crystalline structure and RS content, reaching up to 25.45% and 57.37%, respectively. Overall, this study offers valuable insights into the design of starch-polyphenols complexes with a high RS content.

Asymmetric Pd/Organoboron-Catalyzed Site-Selective Carbohydrate Functionalization with Alkoxyallenes Involving Noncovalent Stereocontrol.

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

Rational construction of perylenequinone annulated porphyrins via cycloaddition reactions

Acenequinone-fused porphyrins show remarkable long wavelength absorption, low-lying LUMO orbital and uniform π,π-stacking, enabling the potential applications as opto-electronic materials and catalysts. At present, the synthesis of large quinone fused porphyrins remains challenging. To address this, the cycloaddition reactions of naphthoquinone-fused porphyrin (Ni4NQ), followed by oxidative aromatization, have been employed. Through Diels-Alder reaction with perylenes in the presence of chloranil, a series of perylenequinone-fused porphyrins (1Ni–4Ni) have been synthesized with an overall yield above 70 %. Later, the tri-adduct 3Ni underwent 1,3-dipolar cycloaddition with nitrile oxide and the following DDQ oxidation to outcome the unsymmetrical tetra-adduct 5Ni. Although the peripheral perylenequinones fusion in 1Ni–4Ni has limited impact on the absorption with respect to the naphthoquinone-fused counterpart Ni4NQ, introduction of an isoxazole via 1,3-cycloaddition (5Ni) leads to a bathochromic Q band. This result has been rationalized by theoretical calculations. Additionally, the incorporation of perylenequinone units gives rise to intense intermolecular π,π-stacking and CH-π interactions within the crystal packing. The self-assembly behavior using a good/bad solvent strategy are structural dependence. The tri-perylenequinone-fused porphyrins 3Ni formed spherical architecture, while tetraperylenequinone-fused porphyrin 4Ni afforded cubic or petal-type assemblies.

In silico study on graphene quantum dots modified with various functional groups inhibiting α‑synuclein dimerization

Hypothesis: Graphene quantum dots (GQDs) with various functional groups are hypothesized to inhibit the α-synuclein (αS) dimerization, a crucial step in Parkinson’s disease pathogenesis. The potential of differently functionalized GQDs is systematically explored.Experiments: All-atom replica-exchange molecular dynamics simulations (accumulating to 75.6 μs) in explicit water were performed to study the dimerization of the αS non-amyloid component region and the influence of GQDs modified with various functional groups. Conformation ensemble, binding behavior, and free energy analysis were conducted.Findings: All studied GQDs inhibit β-sheet and backbone hydrogen bond formation in αS dimers, leading to looser oligomeric conformations. Charged GQDs severely impede the growth of extended β-sheets by providing extra contact surface. GQD binding primarily disrupts αS inter-peptide interactions through π-π stacking, CH-π interactions, and for charged GQDs, additionally through salt-bridge and hydrogen bonding interactions. GQD-COO– showed the most optimal inhibitory effect, binding mode, and intensity, which holds promise for the development of nanomedicines targeting amyloid aggregation in neurodegenerative diseases.

Molecular docking and molecular dynamics simulation decoding molecular mechanism of EDCs binding to hERRγ.

Human estrogen-related receptor γ (hERRγ) is a key protein involved in various endocrines and metabolic signaling. Numerous environmental endocrine-disrupting chemicals (EDCs) can impact related physiological activities through receptor signaling pathways. Focused on hERRγ with 4-isopropylphenol, bisphenol-F (BPF), and BP(2,2)(Un) complexes, we executed molecular docking and multiple molecular dynamics (MD) simulations along with molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) and solvation interaction energy (SIE) calculation to study the detailed dynamical structural characteristics and interactions between them. Molecular docking showed that hydrogen bonds and hydrophobic interactions were the prime interactions to keep the stability of BPF-hERRγ and hERRγ-BP(2,2)(Un) complexes. Through MD simulations, we observed that all complexes reach equilibrium during the initial 50ns of simulation, but these three EDCs lead to local structure changes in hERRγ. Energy results further identified key residues L268, V313, L345, and F435 around the binding pockets through CH-π, π-π, and hydrogen bonds interactions play an important stabilizing role in the recognition with EDCs. And most noticeable of all, hydrophobic methoxide groups in BP(2,2)(Un) is useful for decreasing the binding ability between EDCs and hERRγ. These results may contribute to evaluate latent diseases associated with EDCs exposure at the micro level and find potential substitutes. Autodock4.2 was used to conduct the molecular docking, sietraj program was performed to calculate the energy, and VMD software was used to visualize the structure. Amber18 was conducted to perform the MD simulation and other analyses.

A Computational and Chemical Design Strategy for Manipulating Glycan-Protein Recognition.

Glycans are complex biomolecules that encode rich information and regulate various biological processes, such as fertilization, host-pathogen binding, and immune recognition, through interactions with glycan-binding proteins. A key driving force for glycan-protein recognition is the interaction between the π electron density of aromatic amino acid side chains and polarized C─H groups of the pyranose (termed the CH-π interaction). However, the relatively weak binding affinity between glycans and proteins has hindered the application of glycan detection and imaging. Here, computational modeling and molecular dynamics simulations are employed to design a chemical strategy that enhances the CH-π interaction between glycans and proteins by genetically incorporating electron-rich tryptophan derivatives into a lectin PhoSL, which specifically recognizes core fucosylated N-linked glycans. This significantly enhances the binding affinity of PhoSL with the core fucose ligand and enables sensitive detection and imaging of core fucosylated glycans in vitro and in xenograft tumors in mice. Further, the study showed that this strategy is applicable to improve the binding affinity of GafD lectin for N-acetylglucosamine-containing glycans. The approach thus provides a general and effective way to manipulate glycan-protein recognition for glycoscience applications.

On-Surface Fabrication toward Polar 2D Macromolecular Crystals.

Polar 2D macromolecular structures have attracted significant attention because of their ferroelectricity and ferro-magnetism. However, it is challenging to synthesize them experimentally because dipoles or spins of these macromolecules tend to cancel each other. So far, there has been no successful strategy for assembling macromolecules in a unidirectional manner, achieving stereoregular polymerization on metal surfaces, and creating polar 2D polymer crystals. Recent progress in molecular assembly, on-surface polymer synthesis, and direct control of molecules using electric field applications provides an opportunity to develop such strategies. In this regard, we first review past studies on chiral and achiral molecular assembly, on-surface polymer synthesis, and orientation control of polar molecules. Then, we discuss our newly developed approach called "vectorial on-surface synthesis", which is based on "dynamic chirality" of compass precursors, stereoselective polymerization, and favorable interchain interactions originating from CH-π interactions. Finally, we conclude with a prospective outlook.

Organic-Inorganic Hybrid Glasses of Atomically Precise Nanoclusters.

Organic-inorganic atomically precise nanoclusters provide indispensable building blocks for establishing structure-property links in hybrid condensed matter. However, robust glasses of ligand-protected nanocluster solids have yet to be demonstrated. Herein, we show [Cu4I4(PR3)4] cubane nanoclusters coordinated by phosphine ligands (PR3) form robust melt-quenched glasses in air with reversible crystal-liquid-glass transitions. Protective phosphine ligands critically influence the glass formation mechanism, modulating the glasses' physical properties. A hybrid glass utilizing ethyldiphenylphosphine-based nanoclusters, [Cu4I4(PPh2Et)4], exhibits superb optical properties, including >90% transmission in both visible and near-infrared wavelengths, negligible self-absorption, near-unity quantum yield, and high light yield. Experimental and theoretical analyses demonstrate the structural integrity of the [Cu4I4(PPh2Et)4] nanocluster, i.e., iodine-bridged tetranuclear cubane, has been fully preserved in the glass state. The strong internanocluster CH-π interactions found in the [Cu4I4(PPh2Et)4] glass and subsequently reduced structural vibration account for its enhanced luminescence properties. Moreover, this highly transparent glass enables performant X-ray imaging and low-loss waveguiding in fibers drawn above the glass transition. The discovery of "nanocluster glass" opens avenues for unraveling glass formation mechanisms and designing novel luminescent glasses of well-defined building blocks for advanced photonics.

13 Cβ-Valine and 13 Cγ-Leucine Methine Labeling To Probe Protein Ligand Interaction.

Precise information regarding the interaction between proteins and ligands at molecular resolution is crucial for effectively guiding the optimization process from initial hits to lead compounds in early stages of drug development. In this study, we introduce a novel aliphatic side chain isotope-labeling scheme to directly probe interactions between ligands and aliphatic sidechains using NMR techniques. To demonstrate the applicability of this method, we selected a set of Brd4-BD1 binders and analyzed 1 H chemical shift perturbation resulting from CH-π interaction of Hβ -Val and Hγ -Leu as CH donors with corresponding ligand aromatic moieties as π acceptors.

Revealing the Role of N Heteroatoms in Noncovalent Aromatic Interactions by Ultrafast Intermolecular Coulombic Decay.

Despite the widely recognized importance of noncovalent interactions involving aromatic rings in many fields, our understanding of the underlying forces and structural patterns, especially the impact of heteroaromaticity, is still incomplete. Here, we investigate the relaxation processes that follow inner-valence ionization in a range of molecular dimers involving various combinations of benzene, pyridine, and pyrimidine, which initiate an ultrafast intermolecular Coulombic decay process. Multiparticle coincidence momentum spectroscopy, combined with ab initio calculations, enables us to explore the principal orientations of these fundamental dimers and, thus, to elucidate the influence of N heteroatoms on the relative preference of the aromatic π-stacking, H-bonding, and CH-π interactions and their dependence on the number of nitrogen atoms in the rings. Our studies reveal a sensitive tool for the structural imaging of molecular complexes and provide a more complete understanding of the effects of N heteroatoms on the noncovalent aromatic interactions at the molecular level.

Direct synthesis of chiral β-arylamines via additive-free asymmetric reductive amination enabled by tunable bulky phosphoramidite ligands.

This report describes an additive-free iridium-catalyzed direct asymmetric reductive amination that enables the efficient synthesis of chiral β-arylamines, which are important pharmacophores present in a wide variety of pharmaceutical drugs. The reaction makes use of bulky and tunable phosphoramidite ligands for high levels of enantiomeric control, even for alkylamino coupling partners which lack secondary coordinating sites. The synthetic value of this succinct procedure is demonstrated by single-step synthesis of multiple drugs, analogs and key intermediates. Mechanistic investigations reveal an enamine-reduction pathway, in which H-bonding, steric repulsion, and CH-π and electrostatic interactions play important roles in defining the spatial environment for the "outer-sphere" hydride addition.

Amide-derived enols in enol-Ugi reactions: expanding horizons for peptidomimetic scaffold synthesis.

A highly efficient enol-Ugi reaction of β,β-diketoamides has been developed using a novel non-heterocyclic amide-stabilised enol. This approach enables a broad reaction scope, affording β-enaminoamide peptidomimetics with constrained conformations due to CH-π interaction and C(sp3)H⋯O hydrogen bonding. Notably, the use of a five-membered cyclic enol is crucial for achieving stable products in excellent yields. This work highlights the potential of the enol-Ugi reaction for constructing diverse peptidomimetic scaffolds.

Confinement effects on the structure and reactivity of encapsulated buckybowls in cycloparaphenylene.

We theoretically investigated the host-guest chemistry between belt-like cycloparaphenylenes (CPPs) and entrapped bowl-shaped sumanene and corannulene. Density functional theory calculations show that the buckybowls can be stabilized in a CPP host with an appropriately sized cavity (e.g., [10]CPP) through multi-site CH-π interactions. Arising from the confined intermolecular interactions within the cavity, the restrictive buckybowls display novel reactivity distinct from that in their free state.

Cooling rate uncovers epimer-dependent supramolecular organization of carbohydrate amphiphiles.

We show distinct CH-π interactions and assembly pathways for the amphiphile N-(fluorenylmethoxycarbonyl)-galactosamine and its epimer N-(fluorenylmethoxycarbonyl)-glucosamine. These differences result in the formation of supramolecular nanofibrous systems with opposite chirality. Our results showcase the importance of the carbohydrates structural diversity for their specific biointeractions and the opportunity that their ample interactome offers for synthesis of versatile and tunable supramolecular (bio) materials.

Helicity control of a polyaromatic coordination capsule through stereoselective CH-π interactions.

Although square-planar ML4 units are essential building blocks for coordination cages and capsules, the non-covalent control of the chirality and helicity of the resultant nanostructures is quite difficult. Here we report the helicity control of an M2L4 polyaromatic capsule, formed from metal ions with square-planar coordination geometry and bent bispyridine ligands, through stereoselective CH-π interactions with monosaccharide derivatives. Thanks to host-guest CH-π multi-interactions, one molecule of various permethylated monosaccharides is quantitatively bound by the capsule in water (K a up to >108 M-1). In the polyaromatic cavity, among them, the selective binding of a β-glucose derivative (>80 : 20 ratio) is demonstrated from a mixture of the α/β-glucoses, through the equatorial-selective recognition of the anomeric (C1) group. A similar stereoselective binding is accomplished from an α/β-galactose mixture. Interestingly, single equatorial/axial configurations on the bound monosaccharides can regulate the helical conformation of the capsule in water, confirmed by CD, NMR, and theoretical analyses. An intense capsule-based Cotton effect is exclusively observed upon encapsulation of the permethylated α-glucose (>20-fold enhancement as compared to the β-glucose derivative), via the induction of a single-handed host helicity to a large extent. Inverse capsule helicity is induced by the binding of a β-galactose derivative under the same conditions.

Novel autosomal dominant TMC1 variants linked to hearing loss: insight into protein-lipid interactions

BackgroundTMC1, which encodes transmembrane channel-like protein 1, forms the mechanoelectrical transduction (MET) channel in auditory hair cells, necessary for auditory function. TMC1 variants are known to cause autosomal dominant (DFNA36) and autosomal recessive (DFNB7/11) non-syndromic hearing loss, but only a handful of TMC1 variants underlying DFNA36 have been reported, hampering analysis of genotype-phenotype correlations.MethodsIn this study, we retrospectively reviewed 338 probands in an in-house database of genetic hearing loss, evaluating the clinical phenotypes and genotypes of novel TMC1 variants associated with DFNA36. To analyze the structural impact of these variants, we generated two structural models of human TMC1, utilizing the Cryo-EM structure of C. elegans TMC1 as a template and AlphaFold protein structure database. Specifically, the lipid bilayer-embedded protein database was used to construct membrane-embedded models of TMC1. We then examined the effect of TMC1 variants on intramolecular interactions and predicted their potential pathogenicity.ResultsWe identified two novel TMC1 variants related to DFNA36 (c.1256T > C:p.Phe419Ser and c.1444T > C:p.Trp482Arg). The affected subjects had bilateral, moderate, late-onset, progressive sensorineural hearing loss with a down-sloping configuration. The Phe419 residue located in the transmembrane domain 4 of TMC1 faces outward towards the channel pore and is in close proximity to the hydrophobic tail of the lipid bilayer. The non-polar-to-polar variant (p.Phe419Ser) alters the hydrophobicity in the membrane, compromising protein-lipid interactions. On the other hand, the Trp482 residue located in the extracellular linker region between transmembrane domains 5 and 6 is anchored to the membrane interfaces via its aromatic rings, mediating several molecular interactions that stabilize the structure of TMC1. This type of aromatic ring-based anchoring is also observed in homologous transmembrane proteins such as OSCA1.2. Conversely, the substitution of Trp with Arg (Trp482Arg) disrupts the cation-π interaction with phospholipids located in the outer leaflet of the phospholipid bilayer, destabilizing protein-lipid interactions. Additionally, Trp482Arg collapses the CH-π interaction between Trp482 and Pro511, possibly reducing the overall stability of the protein. In parallel with the molecular modeling, the two mutants degraded significantly faster compared to the wild-type protein, compromising protein stability.ConclusionsThis results expand the genetic spectrum of disease-causing TMC1 variants related to DFNA36 and provide insight into TMC1 transmembrane protein-lipid interactions.

Cooperative supramolecular polymerization of styrylpyrenes for color-dependent circularly polarized luminescence and photocycloaddition

Developing facile and efficient methods to obtain circularly polarized luminescence (CPL) materials with a large luminescence dissymmetry factor (glum) and fluorescence quantum yield (ΦY) is attractive but still challenging. Herein, supramolecular polymerization of styrylpyrenes (R/S-PEB) is utilized to attain this aim, which can self-assemble into helical nanoribbons. Benefiting from the dominant CH-π interactions between the chromophores, the supramolecular solution of S-PEB shows remarkable blue-color CPL property (glum: 0.011, ΦY: 69%). From supramolecular solution to gel, the emission color (blue to yellow-green) and handedness of CPL (glum: –0.011 to +0.005) are concurrently manipulated, while the corresponding supramolecular chirality maintains unchanged, representing the rare example of color-dependent CPL materials. Thanks to the supramolecular confine effect, the [2 + 2] cycloaddition reaction rate of the supramolecular solution is 10.5 times higher than that of the monomeric solution. In contrast, no cycloaddition reaction occurs for the gel and assembled solid samples. Our findings provide a vision for fabricating multi-modal and high-performance CPL-active materials, paving the way for the development of advanced photo-responsive chiral systems.

Enzymatic Dimerization-Induced Self-Assembly of Alanine-Tyramine Conjugates into Versatile, Uniform, Enzyme-Loaded Organic Nanoparticles.

Herein, we report a novel enzymatic dimerization-induced self-assembly (e-DISA) procedure that converts alanine-tyramine conjugates into highly uniform enzyme-loaded nanoparticles (NPs) or nanocontainers by the action of horseradish peroxidase (HRP) in an aqueous medium under ambient conditions. The NP formation was possible with both enantiomers of alanine, and the average diameter could be varied from 150 nm to 250 nm (with a 5-12 % standard deviation of as-prepared samples) depending on the precursor concentration. About 60 % of the added HRP enzyme was entrapped within the NPs and was subsequently utilized for post-synthetic modification of the NPs with phenolic compounds such as tyramine or tannic acid. One-pot multi-enzyme entrapment of glucose oxidase (GOx) and peroxidase (HRP) within the NPs was also achieved. These GOx-HRP loaded NPs allowed multimodal detection of glucose, including that present in human saliva, with a limit of detection (LoD) of 740 nM through fluorimetry. The NPs exhibited good cytocompatibility and were stable to changes in pH (acidic to basic), temperature, ultrasonication, and even the presence of organic solvent (EtOH) to a certain extent, since they are stabilized by intermolecular hydrogen bonding, π-π, and CH-π interactions. The proposed e-DISA procedure can be widely expanded through the design of diverse enzyme-responsive precursors.

Biomimetic Helical Hydrogen Bonded Organic Framework Membranes for Efficient Uranium Recovery from Seawater.

Inspired by the uranyl-imidazole interactions via nitrogen's (N's) of histidine residues in single helical protein assemblies with open framework geometry that allows through migration/coordination of metal ions. Here, preliminary components of a stable hydrogen-bonded organic framework (HOF) are designed to mimic the stable single helical open framework with imidazole residues available for Uranium (U) binding. The imidazolate-HOF (CSMCRIHOF2-S) is synthesized with solvent-directed H-bonding in 1D array and tuned hydrophobic CH-π interactions leading to single helix pattern having enhanced hydrolytic stability. De-solvation led CSMCRIHOF2-P with porous helical 1D channels are transformed in a freestanding thin film that showcased improved mass transfer and adsorption of uranyl carbonate. CSMCRIHOF2-P thin film can effectively extract ≈14.8mgg-1 in 4 weeks period from natural seawater, with >1.7 U/V (Uranium to Vanadium ratio) selectivity. This strategy can be extended for rational designing of hydrolytically stable, U selective HOFs to realize the massive potential of the blue economy toward sustainable energy.