Molecular Architecture Research Articles

Molecular engineering of tethered bilayer lipid membranes for impedimetric detection of pore-forming toxins

Tethered bilayer lipid membranes (tBLMs) with two different molecular architectures were investigated in the context of their utility for biosensing of pore-forming toxins (PFTs). The different architectures were achieved by using two back-filler molecules of different chain length to act as surface diluents for the molecular anchors [20-tetradecyloxy-3,6,9,12,15,18,22-heptaoxahexatricontane-1-thiol (WC14)] that ensure immobilization of the phospholipid bilayers on a solid conductive (metal, such as gold) support. The back-filler molecules were β-mercaptoethanol (BME) and HS(CH2)3(CH2CH2O)5H thiol (C3EO5H). In the case of BME, the submembrane space separating solid surface from attached bilayer (typically 1-2 nm thick) is populated with the ice-like, presumably low entropy and low dielectric constant water, however, the water fraction in the submembrane is high. Much bulkier C3EO5H back-filler renders less space for water in the submembrane, however, it is populated with more mobile water molecules resulting in higher dielectric constant. These two opposing effects result in similar submembrane specific conductances, i.e., the specific electrochemical impedance spectral (EIS) characteristics of the tBLMs and their variation, upon exposure to and reorganization with, the pore-forming toxin (PFT), alpha-hemolysin, occur in the same frequency range for both back-fillers. Significantly, the sensitivity of the C3EO5H-containing tBLMs to PFT is approximately 7–8 times higher than that of the BME-containing surface constructs. At least two physical phenomena contribute to this difference. The bulkier C3EO5H back-fillers facilitate the formation of nanoclusters of the molecular anchors, WC14, with cluster sizes ranging from 20–120 nm. These highly anchor-clustered, “patchy” tBLMs, consequently exhibit other domains devoid, or nearly so, of anchors, resulting in lowering the tBLM global 2-D viscosity by a factor of 3. Thus, a major conclusion of this study is that lower tBLM 2D fluidity increases the sensitivity of tBLMs to PFTs.

Electrochemical non-enzymatic glucose biosensors based on Au-thiol-linked molecular architectures

In this work, an electrochemical non-enzymatic glucose sensor consisting of di-methanethiol-grafted poly (3,4-propylenedioxythiophene), gold nanoparticles (Au NPs), and reduced graphene oxide (rGO) was synthesized by a one-step method through Au-S chemisorption. The structure and morphology of the as-prepared poly (ProDOT-(MeSH)2)/Au/rGO composite were characterized by FT-IR, XRD, EDX, TEM, SEM, and XPS, and the electrochemical performance of the composite was investigated by cyclic voltammetry (CV) and differential pulse voltammetry (DPV) on glassy carbon electrode (GCE). The results show that because of the hydrogen bond interaction between the thiol group on the polymer units and the functional groups on GO, poly (ProDOT-(MeSH)2)/Au/rGO was successfully prepared. In addition, due to the unique morphological structure of the composite and the ability to absorb glucose molecules through hydrogen bonds, the poly(ProDOT-(MeSH)2)/Au/rGO electrode possesses excellent selectivity and unique sensitivity (46.13 μA mM−1 cm−2) for sensing glucose in the linear range of 0.04–16.0 mM with a detection limit of (S/N = 3) 0.01. This paper demonstrates that the poly(ProDOT-(MeSH)2)/Au/rGO composite holds great promise for application as a new glucose sensor in life science.

Molecular architecture and functional dynamics of the pre-incision complex in nucleotide excision repair

Nucleotide excision repair (NER) is vital for genome integrity. Yet, our understanding of the complex NER protein machinery remains incomplete. Combining cryo-EM and XL-MS data with AlphaFold2 predictions, we build an integrative model of the NER pre-incision complex(PInC). Here TFIIH serves as a molecular ruler, defining the DNA bubble size and precisely positioning the XPG and XPF nucleases for incision. Using simulations and graph theoretical analyses, we unveil PInC’s assembly, global motions, and partitioning into dynamic communities. Remarkably, XPG caps XPD’s DNA-binding groove and bridges both junctions of the DNA bubble, suggesting a novel coordination mechanism of PInC’s dual incision. XPA rigging interlaces XPF/ERCC1 with RPA, XPD, XPB, and 5′ ssDNA, exposing XPA’s crucial role in licensing the XPF/ERCC1 incision. Mapping disease mutations onto our models reveals clustering into distinct mechanistic classes, elucidating xeroderma pigmentosum and Cockayne syndrome disease etiology.

A Foldaxane-Based Supramolecular Muscle-Like Switch.

[cn]daisy chain molecular muscle architectures are self-assemblies of hermaphrodite monomers, which usually contain a macrocycle unit linked to a molecular thread that contains sites of interactions - i. e. molecular stations - for the macrocycle. In these multiply threaded structures, altering with control the affinity between macrocycles and stations allows for contraction and extension of the molecule, which is reminiscent of the operation of a muscle. Besides, the field that consists of combining helix and template-containing rods to design foldaxane supramolecular assemblies is still underexplored. By using foldamer units as surrogates for macrocycles, Gan et al. reported the first supramolecular muscle-like foldamer-containing switch that can adopt, after chemical stimulus, either a contracted co-conformational state or a degenerate-like state for which a slow exchange occurred between the contracted and the stretched state.

Air-stable, well-defined palladium–BIAN–NHC chloro dimer: Highly efficient N-Heterocyclic carbene (NHC) catalyst platform for Buchwald–Hartwig C–N cross-coupling reactions

Buchwald-Hartwig amination has become the fundamental method for constructing molecular architectures throughout chemical research, including the synthesis of pharmaceutical agents, natural products, fine chemicals, and advanced materials. Herein, we report air-stable, well-defined palladium–BIAN–NHC chloro dimer, [Pd(BIAN–NHC)(μ-Cl)Cl]2, for Buchwald-Hartwig C–N cross-coupling reactions of aryl halides. This rapidly activating catalyst framework merges the reactive properties of palladium chloro dimers, [Pd(NHC)(μ-Cl)Cl]2, with the structural features of acenaphthoimidazol-2-ylidenes. [Pd(BIAN–NHC)(μ-Cl)Cl]2 is the most reactive Pd(II)–NHC precatalyst to date, undergoing fast activation under both inert atmosphere and aerobic conditions. The catalyst shows an excellent reactivity in Buchwald-Hartwig amination of aryl halides (59 examples), including challenging substrates, diamination and direct functionalization of pharmaceuticals. The steric protection enables high reactivity under both inert atmosphere and aerobic conditions. [Pd(BIAN–IPr)(μ-Cl)Cl]2 should be routinely utilized for the synthesis of C–N bonds to make valuable amines, where it replaces the most commonly deployed at present IPr (IPr = 1,3-bis(2,6-isopropyl)imidazol-2-ylidene).

Hyaluronan‐protein interactions: Lilliput revisited

AbstractHyaluronan (HA) is a huge linear polysaccharide composed entirely of a simple repeating disaccharide that has been preserved unchanged since the evolution of vertebrates ~520 million years ago. It is present in all mammalian tissues, being synthesised within the cell membrane and extruded into the extracellular space where it dictates tissue elasticity, hydration and permeability. HA also directs cell behaviour via engagement with cell surface receptors. These properties allow it to mediate diverse functions in a wide range of physiological and pathological processes, including development, mammalian reproduction and inflammation. There is growing evidence that the way in which the HA biopolymer is differentially organised, through its interaction with a repertoire of HA‐binding proteins (HABPs), is key to the diversity of its biological functions. This review summarises current knowledge of HA‐protein interactions and how their diversity may lead to the formation of HA/protein complexes with distinct molecular architectures that in turn underpin different physical properties and receptor‐mediated effects. Potentially controversial areas such the pro‐inflammatory effects of low molecular weight HA fragments and how short HA‐binding peptides modulate HA function are considered from a molecular perspective.

Molecular Architecture of the Kidney Slit Diaphragm Revealed by Cryo-electron Tomography

Molecular Architecture of the Kidney Slit Diaphragm Revealed by Cryo-electron Tomography

Local molecular and connectomic contributions of tau-related neurodegeneration.

Neurodegeneration in Alzheimer's disease (AD) is known to be mostly driven by tau neurofibrillary tangles. However, both tau and neurodegeneration exhibit variability in their distribution across the brain and among individuals, and the relationship between tau and neurodegeneration might be influenced by several factors. I aimed to map local molecular and connectivity characteristics that affect the association between tau pathology and neurodegeneration. The current study was conducted on the cross-sectional tau-PET and longitudinal T1-weighted MRI scan data of 186 participants from the ADNI dataset including 71 cognitively unimpaired (CU) and 115 mild cognitive impairment (MCI) individuals. Furthermore, the normative molecular profile of a region was defined using neurotransmitter receptor densities, gene expression, T1w/T2w ratio (myelination), FDG-PET (glycolytic index, glucose metabolism, and oxygen metabolism), and synaptic density. I found that the excitatory-inhibitory (E:I) ratio, myelination, synaptic density, glycolytic index, and functional connectivity are linked with deviation in the relationship between tau and neurodegeneration. Furthermore, there was spatial similarity between tau pathology and glycolytic index, synaptic density, and functional connectivity across brain regions. The current study demonstrates that the regional susceptibility to tau-related neurodegeneration is associated with specific molecular and connectomic characteristics of the affected neural systems. I found that the molecular and connectivity architecture of the human brain is linked to the different effects of tau pathology on downstream neurodegeneration.

Design, synthesis, structural analysis, and DFT calculation insights into the molecular architecture of amino substituted 4H-chromene scaffolds

Amino-substituted 4H-chromene scaffolds, comprising nitrogen and oxygen, have garnered significant attention in modern organic chemistry due to their widespread applications in medicinal chemistry, drug discovery, and material sciences. This study demonstrates the synthesis and investigation of a series of 2-amino-3-cyano-4H-chromenes. The molecular structures of these compounds were established using X-ray diffraction, which revealed their supramolecular features. The fused 4H-chromene molecules crystallise in monoclinic and triclinic crystal systems with space groups P-1, P21/c, C2/c, and P21/n. These molecules show interactions like O-H···O, N-H···O, N-H···N, C‑H···O, and C-H···N, along with the π–π stacking and C–H···π arrangements. Hirshfeld surface analysis confirmed the presence of these interactions, and 2D fingerprint plots quantified their contributions. The structural aspects of the compounds, including their optimised molecular geometry and intramolecular hydrogen bonding, were examined using Density Functional Theory (DFT). The constructed structures showed a strong correlation with experimental results. Additionally, the molecular electrostatic potential was studied to understand the energy distribution and chemically reactive regions of the molecules.

Fiber Optic-Mediated Type I Photodynamic Therapy of Brain Glioblastoma Based on an Aggregation-Induced Emission Photosensitizer.

Glioblastoma (GBM) is one of the most lethal human malignancies. The current standard-of-care is highly invasive with strong toxic side effects, leading to poor prognosis and high mortality. As a safe and effective clinical approach, photodynamic therapy (PDT) has emerged as a suitable option for GBM. Nevertheless, its implementation is significantly impeded by the limits of light penetration depth and the firm reliance on oxygen. To overcome these challenges, herein, a promising strategy that harnesses a modified optical fiber and less oxygen-dependent Type I aggregation-induced emission (AIE) photosensitizer (PS) is developed for the first time to realize in vivo GBM treatments. The proposed AIE PS, namely TTTMN, characterized by a highly twisted molecular architecture and a bulky spacer, exhibits enhanced near-infrared emission and strong production of hydroxyl and superoxide radicals at the aggregated state, thus affording efficient fluorescence imaging-guided PDT once formulated into nanoparticles. The inhibition of orthotopic and subcutaneous GBM xenografts provides compelling evidence of the treatment efficacy of Type I PDT irradiated through a tumor-inserted optical fiber. These findings highlight the substantially improved therapeutic outcomes achieved through fiber optic-mediated Type I PDT, positioning it as a promising therapeutic modality for GBM.

Excited-state intramolecular proton transfer (ESIPT) salicylaldehyde Schiff bases: ratiometric sensing of ammonia and biologically relevant ions in solution and solid state

ABSTRACT The intricate molecular architecture of ESIPT salicylaldehyde Schiff bases facilitates dynamic processes, inducing tunable photoluminescent properties. Notably, their halochromic nature, exhibiting colour changes in response to external stimuli, adds a vibrant dimension to their molecular repertoire. This sensitivity extends to environmental factors, making them valuable indicators for alterations in surroundings. The compound (E)-N’-(3,5-dibromo-2-hydroxybenzylidene)-4-methylbenzohydrazide (PTBH) demonstrates exceptional sensitivity to ammonia, enabling real-time detection (LOD = 0.14 nM) in both solution (ratiometric) and the solid state. Moreover, their metal chelation capability allows simultaneous sensing of Mg2+ and Fe2+ ions, addressing environmental hazards. Exploiting molecular recognition, the fluorescent probe serves as sensors for amino acids, opening new avenues in biomedical diagnostics. The study introduces a novel solid-state emissive Schiff base, highlighting its stimuli-responsive photoluminescent properties and diverse applications, emphasising its potential in intelligent fluorescent materials for analytical and sensing technologies.

Molecular architecture of the mammalian 2-oxoglutarate dehydrogenase complex

The 2-oxoglutarate dehydrogenase complex (OGDHc) orchestrates a critical reaction regulating the TCA cycle. Although the structure of each OGDHc subunit has been solved, the architecture of the intact complex and inter-subunit interactions still remain unknown. Here we report the assembly of native, intact OGDHc from Sus scrofa heart tissue using cryo-electron microscopy (cryo-EM), cryo-electron tomography (cryo-ET), and subtomogram averaging (STA) to discern native structures of the whole complex and each subunit. Our cryo-EM analyses revealed the E2o cubic core structure comprising eight homotrimers at 3.3-Å resolution. More importantly, the numbers, positions and orientations of each OGDHc subunit were determined by cryo-ET and the STA structures of the core were resolved at 7.9-Å with the peripheral subunits reaching nanometer resolution. Although the distribution of the peripheral subunits E1o and E3 vary among complexes, they demonstrate a certain regularity within the position and orientation. Moreover, we analyzed and validated the interactions between each subunit, and determined the flexible binding mode for E1o, E2o and E3, resulting in a proposed model of Sus scrofa OGDHc. Together, our results reveal distinctive factors driving the architecture of the intact, native OGDHc.

Molecular architecture of chitin and chitosan-dominated cell walls in zygomycetous fungal pathogens by solid-state NMR

Zygomycetous fungal infections pose an emerging medical threat among individuals with compromised immunity and metabolic abnormalities. Our pathophysiological understanding of these infections, particularly the role of fungal cell walls in growth and immune response, remains limited. Here we conducted multidimensional solid-state NMR analysis to examine cell walls in five Mucorales species, including key mucormycosis causative agents like Rhizopus and Mucor species. We show that the rigid core of the cell wall primarily comprises highly polymorphic chitin and chitosan, with minimal quantities of β-glucans linked to a specific chitin subtype. Chitosan emerges as a pivotal molecule preserving hydration and dynamics. Some proteins are entrapped within this semi-crystalline chitin/chitosan layer, stabilized by the sidechains of hydrophobic amino acid residues, and situated distantly from β-glucans. The mobile domain contains galactan- and mannan-based polysaccharides, along with polymeric α-fucoses. Treatment with the chitin synthase inhibitor nikkomycin removes the β-glucan-chitin/chitosan complex, leaving the other chitin and chitosan allomorphs untouched while simultaneously thickening and rigidifying the cell wall. These findings shed light on the organization of Mucorales cell walls and emphasize the necessity for a deeper understanding of the diverse families of chitin synthases and deacetylases as potential targets for novel antifungal therapies.

Design and synthesis of dicyanoethylene derivatives functionalized with carbazole possessing the properties of obvious aggregation-induced emission and reversible high-contrast mechanofluorochromism

This study devotes to the design, preparation, and examination of two novel D-A structured molecules, designated as CCEDBF and BCCEDBF, which are derived from carbazole unit, dicyanoethylene segment, and dibenzofuran unit. The distinctive D-A molecular architectures and highly twisted spatial configurations of these compounds facilitate pronounced intramolecular charge transfer (ICT) while also imparting robust solid-state luminescence, exhibiting emission efficiencies of 0.518 and 0.739, respectively, and notable aggregation-induced emission (AIE) with AIE factors of 43 and 30. Significantly, both CCEDBF and BCCEDBF demonstrate reversible mechanofluorochromic (MFC) behavior characterized by high fluorescence contrast. Mechanical grinding of the initial powders results in a shift in their emission colors, transitioning from green and yellow-green to yellow and orange-red, respectively, alongside a corresponding shift in emission peaks from 525 nm to 536 nm–558 nm and 597 nm. Powder X-ray diffraction (PXRD) examination of the initially synthesized, mechanically processed, and vaporized samples reveals that the observed fluorescence color change is due to a structural transformation between ordered crystalline and disordered amorphous configurations induced by the application of the external force. The red shift in photoluminescence (PL) spectra post-grinding is attributed to a reduced band gap, driven by factors such as extended π-conjugation length, enhanced planar intramolecular charge transfer (PICT) effect, strengthened π-π interactions and exciton coupling, as well as the increase in the orbitals overlap between neighboring molecular. Moreover, the presence or absence of tert-butyl substituents attaching to the 3- and 6-positions of the carbazole units significantly impacts the photophysical properties of these materials.

Carbon dioxide and hydrogen as building blocks for a sustainable interface of energy and chemistry

Hydrogen as energy vector from renewable sources and carbon dioxide as carbon source are central elements of a future sustainable interface between energy and chemistry. While often viewed merely as “substitutes” for fossil resources, the current article discusses opportunities to open new synthetic pathways and to generate novel molecular architectures for the delivery of the same or even improved functionalities expected from chemical products. Catalysis is the key science and technology in this endeavour and three general principles for the desing of catalytic systems are proposed as guidelines for fundamental research. This article is part of the discussion meeting issue ‘Green carbon for the chemical industry of the future’.

Mapping protein distribution in the canine photoreceptor sensory cilium and calyceal processes by ultrastructure expansion microscopy.

Photoreceptors are highly polarized sensory neurons, possessing a unique ciliary structure known as the photoreceptor sensory cilium (PSC). Vertebrates have two subtypes of photoreceptors: rods, which are responsible for night vision, and cones, which support daylight vision and color perception. Despite identifying functional and morphological differences between these subtypes, ultrastructural analyses of the PSC molecular architecture in rods and cones are still lacking. In this study, we employed ultrastructure expansion microscopy (U-ExM) to characterize the molecular architecture of the PSC in canine retina. We demonstrated that U-ExM is applicable to both non-frozen and cryopreserved retinal tissues with standard paraformaldehyde fixation. Using this validated U-ExM protocol, we revealed the molecular localization of numerous ciliopathy-related proteins in canine photoreceptors. Furthermore, we identified significant architectural differences in the PSC, ciliary rootlet, and calyceal processes between canine rods and cones. These findings pave the way for a better understanding of alterations in the molecular architecture of the PSC in canine models of retinal ciliopathies.

As Aggregation‐Induced Emission Meets with Noncovalent Conformational Locks: Subtly Regulating NIR‐II Molecules for Multimodal Imaging‐Navigated Synergistic Therapies

Phototheranostics is growing into a sparking frontier in disease treatment. Developing single molecular species synchronously featured by powerful absorption capacity, superior second near‐infrared (NIR‐II) fluorescence and prominent photothermal conversion ability is highly desirable for phototheranostics, yet remains formidably challenging. In this work, we propose a molecular design philosophy that the integration of noncovalent conformational locks (NoCLs) with aggregation‐induced emission (AIE) in a single formulation is able to boost multiple photophysical properties for efficient phototheranostics. The introduction of NoCLs skeleton with conformation‐locking feature in the center of molecular architecture indeed elevates the structural planarity and rigidity, which simultaneously promotes the absorption capacity and bathochromic‐shifts the emission wavelength centered in NIR‐II region. Meanwhile, the AIE tendency mainly originated from flexibly propeller‐like geometry at the ends of molecular architecture eventually endows the molecule with satisfactory emission intensity and photothermal conversion in aggregates. Consequently, by utilizing the optimized molecule, unprecedented performance on NIR‐II fluorescence‐photoacoustic‐photothermal trimodal imaging‐guided photothermal‐chemo synergistic therapy is demonstrated by the precise tumor diagnosis and complete tumor ablation.

As Aggregation-Induced Emission Meets with Noncovalent Conformational Locks: Subtly Regulating NIR-II Molecules for Multimodal Imaging-Navigated Synergistic Therapies.

Phototheranostics is growing into a sparking frontier in disease treatment. Developing single molecular species synchronously featured by powerful absorption capacity, superior second near-infrared (NIR-II) fluorescence and prominent photothermal conversion ability is highly desirable for phototheranostics, yet remains formidably challenging. In this work, we propose a molecular design philosophy that the integration of noncovalent conformational locks (NoCLs) with aggregation-induced emission (AIE) in a single formulation is able to boost multiple photophysical properties for efficient phototheranostics. The introduction of NoCLs skeleton with conformation-locking feature in the center of molecular architecture indeed elevates the structural planarity and rigidity, which simultaneously promotes the absorption capacity and bathochromic-shifts the emission wavelength centered in NIR-II region. Meanwhile, the AIE tendency mainly originated from flexibly propeller-like geometry at the ends of molecular architecture eventually endows the molecule with satisfactory emission intensity and photothermal conversion in aggregates. Consequently, by utilizing the optimized molecule, unprecedented performance on NIR-II fluorescence-photoacoustic-photothermal trimodal imaging-guided photothermal-chemo synergistic therapy is demonstrated by the precise tumor diagnosis and complete tumor ablation.

Metal-free ring-opening polymerization for the synthesis of biocompatible star-shaped block copolymers with controllable architecture

Star-shaped block copolymers (SBCs) have sparked interest as efficient cargo carriers due to their high loading capacity, decreased burst effects through sustained release, and maintained stability in dilute aqueous solution. Despite these advantages, the practical usage of SBCs is hindered by their challenging synthesis processes that often utilize metal-based catalysts at high temperatures. Herein we report the tailored synthesis of 3-, 4-, and 6-arm polycaprolactone-b-poly(ethylene glycol), PCL-b-PEG, SBCs using diphenyl phosphate as a friendlier, more sustainable non-metallic catalyst. Nuclear magnetic resonance (NMR) analysis confirms the molecular architecture of SBCs and gel permeation chromatography (GPC) is used to elucidate trends in molar mass when the number of arms within the SBCs is tuned, while dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) studies provide insights into aggregation behavior. Critical aggregation concentration (CAC) values, as measured by fluorescence spectroscopy, demonstrated that the 4-arm and 6-arm SBCs have greater stability than the 3-arm SBC. Biocompatibility assessment indicated minimal cytotoxicity of the nanoaggregates, even at high concentration, making these PCL-b-PEG SBCs potentially safe and sustainable vehicles for biomedical release applications.

Cannabinol (CBN) Influences the Ion Channels and Synaptic-Related Genes in NSC-34 Cell Line: A Transcriptomic Study.

Neurological disorders such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, and schizophrenia are associated with altered neuronal excitability, resulting from dysfunctions in the molecular architecture and physiological regulation of ion channels and synaptic transmission. Ion channels and synapses are regarded as suitable therapeutic targets in modern pharmacology. Cannabinoids have received great attention as an original therapeutic approach for their effects on human health due to their ability to modulate the neurotransmitter release through interaction with the endocannabinoid system. In our study, we explored the effect of cannabinol (CBN) through next-generation sequencing analysis of NSC-34 cell physiology. Our findings revealed that CBN strongly influences the ontologies related to ion channels and synapse activity at all doses tested. Specifically, the genes coding for calcium and potassium voltage-gated channel subunits, and the glutamatergic and GABAergic receptors (Cacna1b, Cacna1h, Cacng8, Kcnc3, Kcnd1, Kcnd2, Kcnj4, Grik5, Grik1, Slc17a7, Gabra5), were up-regulated. Conversely, the genes involved into serotoninergic and cholinergic pathways (Htr3a, Htr3b, Htr1b, Chrna3, Chrnb2, Chrnb4), were down-regulated. These findings highlight the influence of CBN in the expression of genes involved into ion influx and synaptic transmission.