Charged Molecules Research Articles

Charge-based immunoreceptor signalling in health and disease.

Immunoreceptors have crucial roles in sensing environmental signals and initiating immune responses to protect the host. Dysregulation of immunoreceptor signalling can therefore lead to a range of diseases, making immunoreceptor-based therapies a promising frontier in biomedicine. A common feature of various immunoreceptors is the basic-residue-rich sequence (BRS), which is a largely unexplored aspect of immunoreceptor signalling. The BRS is typically located in the cytoplasmic juxtamembrane region of immunoreceptors, where it forms dynamic interactions with neighbouring charged molecules to regulate signalling. Loss or gain of the basic residues in an immunoreceptor BRS has been linked to severe human diseases, such as immunodeficiency and autoimmunity. In this Perspective, we describe the role of BRSs in various immunoreceptors, elucidating their signalling mechanisms and biological functions. Furthermore, we highlight pathogenic mutations in immunoreceptor BRSs and discuss the potential of leveraging BRS signalling in engineered T cell-based therapies.

Fluorescence from a single-molecule probe directly attached to a plasmonic STM tip

The scanning tunneling microscope (STM) provides access to atomic-scale properties of a conductive sample. While single-molecule tip functionalization has become a standard procedure, fluorescent molecular probes remained absent from the available tool set. Here, the plasmonic tip of an STM is functionalized with a single fluorescent molecule and is scanned on a plasmonic substrate. The tunneling current flowing through the tip-molecule-substrate junction generates a narrow-line emission of light corresponding to the fluorescence of the negatively charged molecule suspended at the apex of the tip, i.e., the emission of the excited molecular anion. The fluorescence of this molecular probe is recorded for tip-substrate nanocavities featuring different plasmonic resonances, for different tip-substrate distances and applied bias voltages, and on different substrates. We demonstrate that the width of the emission peak can be used as a probe of the exciton-plasmon coupling strength and that the energy of the emitted photons is governed by the molecule interactions with its environment. Additionally, we theoretically elucidate why the direct contact of the suspended molecule with the metallic tip does not totally quench the radiative emission of the molecule.

Electrostatic Assembly of Gold Nanoclusters in Reverse Emulsion Enabling Nanoassemblies with Tunable Structure and Size for Enhanced NIR-II Fluorescence Imaging.

The precise control of the assembly structure and size of gold nanoclusters (AuNCs) can potentially amplify their near-infrared II (NIR-II) fluorescence imaging and targeting properties. However, the conventional electrostatic assembly of AuNCs and charged molecules faces challenges in balancing the inherent electrostatic repulsions among charged units and regulating the diffusion of assembly units. These difficulties limit precise control over assembly size and structure, along with limited options for coassembled molecules, thereby restricting imaging properties and targeting capability. To circumvent this challenge, we developed a reverse emulsion-confined electrostatic assembly method. This technique efficiently constructs AuNC nanoassemblies with diverse coassembled molecules, allowing for the fine-tuning of assembly size and structure, including both core-satellite and homogeneous AuNC nanoassemblies. The development of two distinct nanoassemblies can be partially attributed to the varying diffusive rates of AuNCs or the AuNCs/polymer complex within the fused emulsion droplets. This variance arises from steric hindrances encountered during the emulsion fusion process. Interestingly, core-satellite nanoassemblies exhibit the strongest NIR-II fluorescence enhancement. Finally, the introduction of a hyaluronic acid coating on the surfaces of nanoassemblies with varying sizes enables the nanoprobes to achieve enhanced lymph node imaging through size modulation and macrophage targeting, which are used for surgical navigation to remove lymph node metastases. We envision that this self-assembly strategy can be extended to a wide range of electrostatic assembly systems for the development of multicomponent functional materials.

Macrocycle Unidirectional Transport Along a Linear Molecule by a Two-Step Chemical Reaction Sequence.

Chemical systems displaying directional motions are relevant to the operation of artificial molecular machines. Herein we present the functioning of a molecule capable of transporting a cyclic species in a preferential direction. Our system is based on a linear, non-symmetric, positively charged molecule. This cation integrates into its structure two different reactive regions. On one side features a bulky ester group that can be exchanged by a smaller substituent; the other extreme contains an acid/base responsive moiety that plays a dual role, as part of the recognition motif and as a terminal group. In the acidic state, a dibenzo-24-crown-8 ether slides into the linear component attracted by the positively charged recognition site. It does this selectively through the extreme that contains the azepanium group, since the other side is sterically hindered. After base addition, intermolecular interactions are lost; however, the macrocycle is unable to escape from the linear component since the energy barrier to slide over the neutral azepane is too large. Therefore, a metastable mechanically interlocked molecule is formed. A second reaction, now on the ester functionality, exchanges the bulky mesityl for a methyl group, small enough to allow macrocycle dissociation, completing the directional transit of the ring along the track.

A microscale soft lithium-ion battery for tissue stimulation

AbstractAdvances in the development of tiny devices with sizes below a few cubic millimeters require a corresponding decrease in the volume of driving power sources. To be minimally invasive, prospective power sources in biomedical devices must be fabricated from soft materials. Previous endeavors with droplet-based devices have produced promising miniature power sources; however, a droplet-based rechargeable battery has remained out of reach. Here we report a microscale soft flexible lithium-ion droplet battery (LiDB) based on the lipid-supported assembly of droplets constructed from a biocompatible silk hydrogel. Capabilities such as triggerable activation, biocompatibility and biodegradability and high capacity are demonstrated. We have used the LiDB to power the electrophoretic translocation of charged molecules between synthetic cells and to mediate the defibrillation and pacing of ex vivo mouse hearts. By the inclusion of magnetic particles to enable propulsion, the LiDB can function as a mobile energy courier. Our tiny versatile battery will thereby enable a variety of biomedical applications.

Physicochemical Properties of Seed Oil Blends and Their Potential for the Creation of Synthetic Oleosomes with Modulated Polarities.

There is an increasing demand within the pharmaceutical and cosmetic industries for biofriendly lipid-based active ingredient delivery systems. Micelles, liposomes, and lipid nanoparticles are currently the most used systems despite their limitations. Oleosomes, also known as lipid droplets, are promising alternatives to the existing strategies. Oleosomes are typically found in plant cells and are characterized by a nonpolar triacylglycerol core surrounded by a phospholipid monolayer punctuated with the protein oleosin. Producing oleosomes synthetically allows the customization of their lipid content, size, protein content, and oil core characteristics, expanding their versatility. Herein we demonstrate a proof of concept for the use of synthetic oleosomes to sequester polar molecules by modulating their core polarity with blends of sunflower and castor oils. The physical properties (density, refractive index, and permittivity) of the oil blends are characterized and demonstrate ideal mixing of the oils, which is supported by molecular dynamics simulations. Spectroscopic examination of the oil blends using fluorescent probes shows that the polarity of oil blends increases as the fraction of castor oil increases. Finally, we show that the uptake of a polar fluorescent probe (NBD-glucose) into synthetic oleosomes is enhanced by increasing the polarity of the oil core, but large charged molecules are excluded from the core regardless of polarity. These experiments show that synthetic oleosomes with tunable oil cores can expand the range of molecules that can be loaded into a biofriendly package as desired for biotechnology applications.

Adsorption dynamics of heavy oil droplets on silica: Effect of asphaltene anionic carboxylic

Understanding the adsorption behavior of asphaltene molecules on the surfaces of oil reservoir solids is essential for optimizing oil recovery processes. This study employed molecular dynamics simulations to investigate the adsorption behavior of oil droplets composed of charged and neutral asphaltenes on silica surfaces. The results revealed that oil droplet containing anionic asphaltene molecules were more likely to adsorb onto silica surfaces and exhibited greater resistance to detachment compared to oil droplet containing neutral asphaltene molecules. Specifically, anionic asphaltene molecules tended to accumulate at the oil-water-silica interface, whereas neutral asphaltene molecules primarily adsorbed near the oil-water interface. These findings provide valuable insights into the differing adsorption dynamics of charged and neutral asphaltene molecules on silica surfaces.

Tuning the atomic ordering of AFI framework with templates charge

In this work, AlPO4-5 (AFI) zeotype materials were synthesized using the microwave approach in the presence of two organic templates i.e. tripropylamine (R) and tetrapropylammonium (R+). The long- and short-range crystalline order of the samples were investigated by considering the effect of the template's charge on the atomic-level ordering of the AFI framework. Using advanced NMR spectroscopy, we shed the light on the importance of templates' role on the organization of the inorganic framework of aluminophosphates. The spectroscopic data clearly show a wider distribution of Al and P environments in the materials synthesized with the charged template (R+) due to the need of hydroxyl groups charge compensators that induce some bridges distortions. When a charged molecule (R+) was used, aluminum appears to be responsible for the charge compensation mechanism via the association of OH groups, impacting the environment of phosphorus as well. The hydroxyl groups needed for charge compensation in samples synthesized with R+ persist after calcination. Consequently, the hydrophilicity of the sample synthesized with R+ features approximatively two times higher values compared to the one synthesized with R.

A microfluidic in vitro method predicting the fate of peptide drugs after subcutaneous administration

For many biopharmaceuticals, subcutaneous (sc) administration is the only viable route. However, there is no in vitro method available accurately predicting the absorption profiles of subcutaneously injected pharmaceuticals. In this work, we show that a recently developed microfluidics method for interaction studies (MIS) has the potential to be useful in this respect. The method utilises the responsiveness of polyelectrolyte microgel networks to oppositely charged molecules as a means to monitor the interaction between peptides and hyaluronic acid (HA), a major constituent of the subcutaneous extracellular matrix. We use the method to determine parameters describing the strength of interaction between peptide and HA as well as the peptide’s aggregation tendency and transport properties in HA networks. The results from MIS studies of the peptide drugs exenatide, pramlintide, vancomycin, polymyxin B, lanreotide, MEDI7219 and AZD2820 are compared with results from measurements with the commercially available SCISSOR system and in vivo absorption and bioavailability data from the literature. We show that both MIS and SCISSOR reveal differences in the peptides’ diffusivity and tendency to aggregate in the presence of HA. We show that MIS is particularly good at discriminating between peptides forming aggregates stabilised by non-electrostatic forces in the presence of HA, and peptides forming complexes stabilised by electrostatic interactions with HA. The method provides two parameters that can be used to quantify the peptides’ aggregation tendency, the one describing the peptide packing density in complexes with HA and the other the apparent diffusivity upon release in a medium of physiological ionic strength and pH. The order of the peptides when ranked by increasing binding strength at pH 7.4 determined with MIS is shown to be in agreement with the order when ranked by the apparent 1st order absorption rate constant (ka) after sc administration in humans: lanreotide (Autogel) < exenatide (IRF) < AZD2820 < pramlintide < lanreotide (IRF) (IRF: Immediate release formulation). A correlation is found between the 1st order release rate constant determined with SCISSOR and ka for lanreotide (Autogel), exenatide and AZD2820. A mechanism relating the magnitude of ka to the peptides’ charge is proposed.

Nutmeg and SPICE: Models and Data for Biomolecular Machine Learning.

We describe version 2 of the SPICE data set, a collection of quantum chemistry calculations for training machine learning potentials. It expands on the original data set by adding much more sampling of chemical space and more data on noncovalent interactions. We train a set of potential energy functions called Nutmeg on it. They are based on the TensorNet architecture. They use a novel mechanism to improve performance on charged and polar molecules, injecting precomputed partial charges into the model to provide a reference for the large-scale charge distribution. Evaluation of the new models shows that they do an excellent job of reproducing energy differences between conformations even on highly charged molecules or ones that are significantly larger than the molecules in the training set. They also produce stable molecular dynamics trajectories and are fast enough to be useful for routine simulation of small molecules.

Singlet oxygen generation by nanoassemblies containing porphyrin macrocycles: Steric and screening effects, energy transfer and competing processes

In this semi-review paper, we discuss some principal aspects that should be taken into account upon quantitative analysis of the interaction with molecular oxygen O2 and the singlet oxygen (1O2 or [Formula: see text] generation by various tetrapyrrolic photosensitizers (including monomers, chemical dimers, triads, pentads and organic-inorganic nanoassemblies). In all cases, the direct experimental measurements of 1O2 emission at [Formula: see text] = 1.27 μ need to be corrected to the solvent influence (refractive indexes, molecular polarizability) on the rate constant of the radiative transition [Formula: see text] in a 1O2 molecule. For porphyrin and chlorin chemical dimers, T1 states quenching by O2 followed by 1O2 generation depends on donor-acceptor interactions between the dimer halves, and extra-ligation effects as well as the spacer flexibility. In the case of self-assembled triads and pentads containing Zn-porphyrin dimers and pyridyl substituted porphyrin free bases (H2P) as extra-ligands, quenching rate constants of H2P T1 states by O2 are smaller compared to those found for individual monomeric H2P molecules which is explained by the spatial screening influence of a strongly quenched Zn-porphyrin dimer in multiporphyrin complexes. Finally, at 293 K for nanoassemblies of two types (semiconductor quantum dots CdSe/ZnS + coordinative linked tetra-pyridyl porphyrins, and semiconductor negatively charged quantum dots AgInS/ZnS + positively charged porphyrin molecules) it was quantitatively shown that non-radiative energy transfer FRET quantum dot [Formula: see text] porphyrin (competing with electron tunneling under conditions of quantum confinement) is only responsible for the singlet oxygen 1O2 generation by nanoassemblies.

Versatile Cell Penetrating Peptide for Multimodal CRISPR Gene Editing in Primary Stem Cells.

CRISPR gene editing offers unprecedented genomic and transcriptomic control for precise regulation of cell function and phenotype. However, delivering the necessary CRISPR components to therapeutically relevant cell types without cytotoxicity or unexpected side effects remains challenging. Viral vectors risk genomic integration and immunogenicity while non-viral delivery systems are challenging to adapt to different CRISPR cargos, and many are highly cytotoxic. The arginine-alanine-leucine-alanine (RALA) cell penetrating peptide is an amphiphilic peptide that self-assembles into nanoparticles through electrostatic interactions with negatively charged molecules before delivering them across the cell membrane. This system has been used to deliver DNAs, RNAs, and small anionic molecules to primary cells with lower cytotoxicity compared to alternative non-viral approaches. Given the low cytotoxicity, versatility, and competitive transfection rates of RALA, we aimed to establish this peptide as a new CRISPR delivery system in a wide range of molecular formats across different editing modalities. We report that RALA was able to effectively encapsulate and deliver CRISPR in DNA, RNA, and ribonucleic protein (RNP) formats to primary mesenchymal stem cells (MSCs). Comparisons between RALA and commercially available reagents revealed superior cell viability leading to higher numbers of transfected cells and the maintenance of cell proliferative capacity. We then used the RALA peptide for the knock-in and knock-out of reporter genes into the MSC genome as well as for the transcriptional activation of therapeutically relevant genes. In summary, we establish RALA as a powerful tool for safer and effective delivery of CRISPR machinery in multiple cargo formats for a wide range of gene editing strategies.

Vibrational spectroscopic interpretation, solvent effect and molecular docking studies of TAAR1 partial agonist RO5263397

Density functional theory studies of TAAR1 (trace amine associated receptor 1) partial agonist RO5263397 carried out with precise and detailed spectroscopic investigation as well as validated experimentally. FT-IR, confocal Raman and UV–visible spectroscopic techniques were used to characterize the compound and corresponding theoretical calculations were carried out using DFT/B3LYP method with 6-311++G (d,p) basis set. Estimated and observed vibrational wavenumbers of the compound were assigned. UV–visible spectrum and FMOs (frontier molecular orbital) analysis reveals that the polarity affects the molecular reactivity and stability of the compound. Donor – acceptor interaction and second order perturbation energy have been explained using natural bond orbital analysis clarify the presence hydrogen bonds in the system. ELF and LOL studies visualises the localized and delocalized electrons in the title compound. RDG analysis evidences the various interactions present in the monomer and dimer of RO5263397. The structural importance of the compound were clearly examined using NMR spectral analysis. The existence of hydrogen bonding is validated by reactive site findings from Mulliken atomic charge distribution and molecule electrostatic potential surface studies. Information about distinct drug-receptor interactions obtained from molecular docking investigation offers the path of further study of molecular activity in various drug-receptor mechanism.

Breakdown of the Total Dipole Moments of Diatomic Molecules into Individual Orbital Contributions.

Quantum chemical results at the CCSD(T)/def2-QZVPP and BP86/def2-QZVPP levels are reported for the neutral and charged diatomic molecules EF, EO- (E = B-Tl), EF+, EO, EN- (E = C-Pb), EO+, and EN (E = N-Bi). The theoretically predicted bond lengths and dipole moments are in good agreement with each other and with the available experimental values. It is shown that the total dipole moment of the molecules can be nicely separated into the contributions of the individual occupied molecular orbitals. The σ lone-pair orbital has a dominating influence on the total dipole moment in the lighter EX systems, where E is an atom of the first or second octal row of the periodic table, but it becomes less influential for the heavier species. The HOMO of the heavy cations PbF+, SbO+, and BiO+ is the degenerate π-bonding orbital, and the σ lone-pair orbital is the HOMO-2. The orbital energies of the (n-1)d AOs of the heavier atoms are in the same range as those of the lowest lying genuine valence orbitals, so the division into nuclear and valence orbitals is not so clear.

Plasmonic Au-MoS2 Nanohybrids Using Pulsed Laser-Induced Photolysis Synthesis for Enhanced Visible-Light Photocatalytic Dye Degradation.

The Au-MoS2 nanocomposites (NCPs) exhibit excellent visible-light photocatalytic activity and potential applications in the photocatalytic degradation of organic dyes. In this study, an Au-MoS2 heterojunction structure with Au nanoparticles (NPs) deposited on MoS2 nanosheets was synthesized via the pulsed laser-induced photolysis method. The influence of Au content on the photocatalytic performance was systematically investigated, and the working mechanism under visible light excitation was elucidated. The optimal Au-MoS2 NCPs exhibited efficient degradation of methylene blue (MB) dye, mainly attributed to the plasmon resonance effect of Au NPs which facilitated the visible light harvesting and hot electron injection. The Au/MoS2 interface promoted the separation and transfer of photogenerated charge carriers. The electrostatic adsorption between positively charged MB molecules and the negatively charged MoS2 surface favored the affinity toward active sites. Furthermore, the photogenerated electrons and holes participated in generating reactive oxygen species such as superoxide and hydroxyl radicals, which initiated the oxidative degradation of MB. The PLIP-introduced Au NPs not only endowed the material with excellent visible light responsivity but also possibly modulated the electronic structure and photocatalytic active sites of MoS2 through an intrinsic effect, providing new insights for further enhancing the photocatalytic performance of Au-MoS2 NCPs.

DC vs AC Electrokinetics-Driven Nanoplasmonic Raman Monitoring of Charged Analyte Molecules in Ionic Solutions.

Electrokinetic surface-enhanced Raman spectroscopy (EK-SERS) is an emerging high-order analytical technique that combines the plasmonic sensitivity of SERS with the electrode interfacial molecular control of electrokinetics. However, previous EK-SERS works primarily focused on non-Faradaic direct current (DC) operation, limiting the understanding of the underlying mechanisms. Additionally, developing reliable EK-SERS devices with electrically connected plasmonic hotspots remains challenging for achieving high sensitivity and reproducibility in EK-SERS measurements. In this study, we investigated the use of two-tier nanolaminate nano-optoelectrode arrays (NL-NOEAs) for DC and alternating current (AC) EK-SERS measurements of charged analyte molecules in ionic solutions. The NL-NOEAs consist of Au/Ag/Au multilayered plasmonic nanostructures on conductive nanocomposite nanopillar arrays (NC-NPAs). We demonstrate that the NL-NOEAs exhibit high SERS enhancement factors (EFs) of ∼106 and can be used to modulate the concentration and orientation of Rhodamine 6G (R6G) molecules at the electrode surface by applying DC and AC voltages. We also performed numerical simulations to investigate the ion and R6G dynamics near the electrode surface under DC and AC voltage modulation. Our results show that AC EK-SERS can provide additional insights into the dynamics of molecular transport and adsorption processes compared to DC EK-SERS. This study demonstrates the potential of NL-NOEAs for developing high-performance EK-SERS sensors for a wide range of applications.

The contribution of porins to enterobacterial drug resistance.

In Enterobacteriaceae, susceptibility to cephalosporins and carbapenems is often associated with membrane and enzymatic barrier resistance. For about 20 years, a large number of Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae presenting ß-lactam resistance have been isolated from medical clinics. In addition, some of the resistant isolates exhibited alterations in the outer membrane porin OmpC-OmpF orthologues, resulting in the complete absence of gene expression, replacement by another porin or mutations affecting channel properties. Interestingly, for mutations reported in OmpC-OmpF orthologues, major changes in pore function were found to be present in the gene encoding for OmpC. The alterations were located in the constriction region of the porin and the resulting amino acid substitutions were found to induce severe restriction of the lumen diameter and/or alteration of the electrostatic field that governs the diffusion of charged molecules. This functional adaptation through porins maintains the entry of solutes necessary for bacterial growth but critically controls the influx of harmful molecules such as β-lactams at a reduced cost. The data recently published show the importance of understanding the underlying parameters affecting the uptake of antibiotics by infectious bacteria. Furthermore, the development of reliable methods to measure the concentration of antibiotics within bacterial cells is key to combat impermeability-resistance mechanisms.

Shape-persistent ladder molecules exhibit nanogap-independent conductance in single-molecule junctions.

Molecular electronic devices require precise control over the flow of current in single molecules. However, the electron transport properties of single molecules critically depend on dynamic molecular conformations in nanoscale junctions. Here we report a unique strategy for controlling molecular conductance using shape-persistent molecules. Chemically diverse, charged ladder molecules, synthesized via a one-pot multicomponent ladderization strategy, show a molecular conductance (d[log(G/G0)]/dx ≈ -0.1 nm-1) that is nearly independent of junction displacement, in stark contrast to the nanogap-dependent conductance (d[log(G/G0)]/dx ≈ -7 nm-1) observed for non-ladder analogues. Ladder molecules show an unusually narrow distribution of molecular conductance during dynamic junction displacement, which is attributed to the shape-persistent backbone and restricted rotation of terminal anchor groups. These principles are further extended to a butterfly-like molecule, thereby demonstrating the strategy's generality for achieving gap-independent conductance. Overall, our work provides important avenues for controlling molecular conductance using shape-persistent molecules.

A universal electrochemical-modulated surface-enhanced Raman scattering platform for the sensitive detection of charged molecules

Electrochemical-modulated surface-enhanced Raman scattering (EC-SERS) integrates the benefits of SERS with electrochemical techniques. By controlling the electrode potential, Raman spectroscopy allows for the analysis of molecules with enhanced sensitivity and selectivity. With its large volume and high sample consumption, the traditional three-electrode electrochemical cell constrains the widespread adoption of EC-SERS. This study developed a versatile EC-SERS platform based on Ag nanowires-modified screen-printed electrode (AgNWs-SPE). Taking advantage of the dual functionality of AgNWs-SPE, this platform facilitates the successful in situ collection and sensitive detection of charged molecules. Experimental findings and theoretical calculations validate the platform's high sensitivity and selectivity mainly regulated by the applied potential, providing a universal approach for the highly sensitive and accurate detection of charged molecules.

Gate-Switchable Molecular Diffusion on a Graphene Field-Effect Transistor.

Controlling the surface diffusion of particles on 2D devices creates opportunities for advancing microscopic processes such as nanoassembly, thin-film growth, and catalysis. Here, we demonstrate the ability to control the diffusion of F4TCNQ molecules at the surface of clean graphene field-effect transistors (FETs) via electrostatic gating. Tuning the back-gate voltage (VG) of a graphene FET switches molecular adsorbates between negative and neutral charge states, leading to dramatic changes in their diffusion properties. Scanning tunneling microscopy measurements reveal that the diffusivity of neutral molecules decreases rapidly with a decreasing VG and involves rotational diffusion processes. The molecular diffusivity of negatively charged molecules, on the other hand, remains nearly constant over a wide range of applied VG values and is dominated by purely translational processes. First-principles density functional theory calculations confirm that the energy landscapes experienced by neutral vs charged molecules lead to diffusion behavior consistent with experiment. Gate-tunability of the diffusion barrier for F4TCNQ molecules on graphene enables graphene FETs to act as diffusion switches.