Small Molecular Complexes Research Articles

One-step nanoscale expansion microscopy reveals individual protein shapes.

The attainable resolution of fluorescence microscopy has reached the subnanometer range, but this technique still fails to image the morphology of single proteins or small molecular complexes. Here, we expand the specimens at least tenfold, label them with conventional fluorophores and image them with conventional light microscopes, acquiring videos in which we analyze fluorescence fluctuations. One-step nanoscale expansion (ONE) microscopy enables the visualization of the shapes of individual membrane and soluble proteins, achieving around 1-nm resolution. We show that conformational changes are readily observable, such as those undergone by the ~17-kDa protein calmodulin upon Ca2+ binding. ONE is also applied to clinical samples, analyzing the morphology of protein aggregates in cerebrospinal fluid from persons with Parkinson disease, potentially aiding disease diagnosis. This technology bridges the gap between high-resolution structural biology techniques and light microscopy, providing new avenues for discoveries in biology and medicine.

Unraveling the Disulfide-Carbonyl n → π* Interactions in a Gas Phase Molecular Complex and Proteins.

The weak contacts between disulfide linkages and carbonyl groups are anticipated to be important in determining the structure and function of enzymes and proteins. However, the characteristics of the disulfide-carbonyl n → π* (nSS → π* C═O) interactions remain unexplored. Herein, we investigated the nSS → π* C═O interactions in the gas phase and in proteins. Rotational spectroscopic investigation of a model complex of allyl methyl disulfide with formaldehyde identified two structures, both of which are stabilized through a dominant nSS → π* C═O interaction. Surveys of the Protein Data Bank revealed the occurrence of 18 675 nSS → π* C═O interactions associated with 15 320 disulfide bonds in 7105 protein structures. Further theoretical analyses characterize the bonding nature of the nSS → π* C═O interactions. This study provides an in-depth understanding of the stabilizing effect of the nSS → π* C═O interactions in small molecular complexes and biomacromolecules.

Identification of potential biomarkers for sepsis based on neutrophil extracellular trap-related genes

Sepsis is a highly lethal disease that poses a serious threat to human health. Increasing evidence indicates that neutrophil extracellular traps (NETs) are key factors in the pathological progression of sepsis. This study aims to screen potential biomarkers for sepsis and delve into their regulatory function in the pathogenesis. We downloaded 6 microarray datasets from the Gene Expression Omnibus (GEO) database, with 4 as the training sets and 2 as the validation sets. NETs-related genes (NRGs) were obtained from relevant literature. Differential expression analysis was performed on four training sets separately. We intersected differentially expressed genes (DEGs) from the four training sets and NRGs, finally resulting in 19 NETs-related sepsis genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) unearthed that NETs-related sepsis genes were majorly abundant in functions and pathways such as defense response to bacterium and Neutrophil extracellular trap formation. Using the PPI network, the MCC algorithm, and the MCODE algorithm in the CytoHubba plugin, 7 sepsis hub genes (ELANE, TLR4, MPO, PADI4, CTSG, MMP9, S100A12) were identified. ROC curve for each Hub gene in the training and validation sets were plotted, which revealed that the Area Under Curve (AUC) values are all greater than 0.6, indicating good classification ability. A total of 349 miRNAs targeting Hub genes were predicted in the mirDIP database, and 620 lncRNAs targeting miRNAs were predicted in the ENCORI database. The ceRNA regulatory network was constructed using Cytoscape software. Finally, we employed the cMAP database to predict small molecular complexes as potentially effective drugs for the treatment of sepsis, such as chloroquine, harpagoside, and PD-123319. In conclusion, this project successfully identified 7 core genes, which may serve as promising candidates for novel sepsis biomarkers. Meanwhile, we constructed a related ceRNA network and predicted potential targeted drugs, providing potential therapeutic targets and treatment strategies for sepsis patients.

Discovering Molecular Coordination Environment Trends for Selective Ion Binding to Molecular Complexes Using Machine Learning.

The design of ion-selective materials with improved separation efficacy and efficiency is paramount, as current technologies fail to meet real-world deployment challenges. Selectivity in these materials can be informed by local ion binding in confined membrane ion channels. In this study, we utilize a data-driven approach to investigate design features in small molecular complexes coordinating ions as simplified models of ion channels. We curate a data set of 563 alkali metal coordinating molecular complexes (i.e., with Li+, Na+, or K+) from the Cambridge Structural Database and calculate differential ion binding energies using density functional theory. Using this information, we probe when and why structures favor exchange with alternate ions. Our analysis reveals that energetic preferences are related to ion size but are largely due to chemical interactions rather than structural reorganization. We identify unique trends in the selectivity for Li+ over other alkali ions, including the presence of N coordination atoms, planar coordination geometry, and small coordinating ring sizes. We use machine learning models to identify the key contributions of both geometric and electronic features in predicting selective ion binding. These physical insights offer preliminary guidance into the design of optimal membranes for ion selectivity.

Highly NIR-II luminescent erbium porphyrinoids

Erbium (Er[Formula: see text] ion exhibits efficient broadband emission at 1.53 [Formula: see text]m (4f optical transition 4I13/2 [Formula: see text] 4I15/2), which is promising to achieve better clarity and deeper penetration depth for biological imaging. However, because of the relatively low luminescent level (4I[Formula: see text], ca. 6500 cm[Formula: see text] and the tendency of being facile to be quenched by high-energy oscillators such as N-H, C-H, or O-H groups, achieving small molecular Er complexes with intense NIR-II luminescence has remained a challenge. In this work, a series of Er[Formula: see text] complexes of porphyrinoids and [Formula: see text]-perhalogenated derivatives caped with auxiliary deuterated Kläui ligands were prepared, namely X-1-Er, X-2-Er and X-cis/trans-3-Er (X = H, F, Cl, Br). Interestingly, most of the [Formula: see text]-perhalogenated Er complexes displayed high overall quantum yields ([Formula: see text] 0.1% in CH2Cl2 and CD2Cl2) and long lifetimes ([Formula: see text] 8 [Formula: see text]s in CH2Cl2 and 11 [Formula: see text]s in CD2Cl2).

Ion-mediated hydrogen-bond rearrangement through tunnelling in the iodide-dihydrate complex.

A microscopic picture of hydrogen-bond structure and dynamics in ion hydration shells remains elusive. Small ion-dihydrate molecular complexes are ideal systems with which to investigate the interplay and competition between ion-water and water-water interactions. Here, state-of-the-art quantum dynamics simulations provide evidence for tunnelling in hydrogen-bond rearrangements in the iodide-dihydrate complex and show that it can be controlled through isotopic substitutions. We find that the iodide ion weakens the neighbouring water-water hydrogen bond, leading to faster water reorientation than in the analogous water trimer. These faster dynamics, which are apparently at odds with the slowdown observed in the first hydration shell of iodide in solution, can be traced back to the presence of a free OH bond in the iodide-dihydrate complex, which effectively triggers the overall structural rearrangements within it. Besides providing indirect support for cooperative hydrogen-bond dynamics in iodide solutions, the analysis presented here suggests that iodide ions may accelerate hydrogen-bond rearrangements at aqueous interfaces, where neighbouring water molecules can be undercoordinated.

Volumetric, viscometric and molecular simulation studies of glycine in aqueous sodium sulphate solutions at different temperatures

The densities and viscosities of Glycine in five aqueous solutions of Sodium Sulphate, were measured in the temperature range from 283.15 to 308.15 K at intervals of 5 K, using a vibrating U-tube densimeter Anton Paar DMA 5000 and the Automatic Microviscosimeter AMVn, respectively. The measured densities were used to calculate the limit-apparent molar volume (Vϕ0), limit-transfer molar volume (ΔtrVφ0)and hydration number (nh). The partial volumes at infinite dilution of the glycine in aqueous solution of sodium sulfate were evaluated through extrapolation at each temperature. The behavior of ΔtrVϕ0 was interpreted in terms of solute–solvent interactions on the basis of the cosphere-overlap model. The hydration numbers were positive and interpreted in terms of dehydration and electrostriction effects. The relative viscosity data were adjusted by least-squares for obtain the Jones-Dole equation coefficients A, B and D. To accompany the experimental results, a series of small molecular complexes simulating the interactions present in the glycine + water/sodium sulfate systems were modeled by the Density Functional Theory with the basis function 6-31G(d). From viscosity dates, the activation parameters of the viscous flow (free molar energy of Gibbs ΔG≠, enthalpy ΔH≠, and entropy ΔS≠) were evaluated. The temperature dependence of the partial molar volume at infinite dilution and the viscosity B coefficient were discussed in terms of the dominant interactions in solution; it was found that the glycine has a making effect in the structure of the solvent, and at infinite dilution ion-solvent interactions are dominant between NH3+ and COO− groups of the amino acid with Na+ and SO42− ions. From the theoretical point of view, the complexes studied turned out to be stable and represent a good approximation to rationalize the intermolecular interactions that occur in glycine + water/sodium sulphate mixtures.

Detection of Small Molecular Complexes at the Plasma Membrane via Temporal Accumulation Analysis

Detection of Small Molecular Complexes at the Plasma Membrane via Temporal Accumulation Analysis

Exploring a multi-scale method for molecular simulation in continuum solvent model: Explicit simulation of continuum solvent as an incompressible fluid.

We explored a multi-scale algorithm for the Poisson-Boltzmann continuum solvent model for more robust simulations of biomolecules. In this method, the continuum solvent/solute interface is explicitly simulated with a numerical fluid dynamics procedure, which is tightly coupled to the solute molecular dynamics simulation. There are multiple benefits to adopt such a strategy as presented below. At this stage of the development, only nonelectrostatic interactions, i.e., van der Waals and hydrophobic interactions, are included in the algorithm to assess the quality of the solvent-solute interface generated by the new method. Nevertheless, numerical challenges exist in accurately interpolating the highly nonlinear van der Waals term when solving the finite-difference fluid dynamics equations. We were able to bypass the challenge rigorously by merging the van der Waals potential and pressure together when solving the fluid dynamics equations and by considering its contribution in the free-boundary condition analytically. The multi-scale simulation method was first validated by reproducing the solute-solvent interface of a single atom with analytical solution. Next, we performed the relaxation simulation of a restrained symmetrical monomer and observed a symmetrical solvent interface at equilibrium with detailed surface features resembling those found on the solvent excluded surface. Four typical small molecular complexes were then tested, both volume and force balancing analyses showing that these simple complexes can reach equilibrium within the simulation time window. Finally, we studied the quality of the multi-scale solute-solvent interfaces for the four tested dimer complexes and found that they agree well with the boundaries as sampled in the explicit water simulations.

Selenocystine against methyl mercury cytotoxicity in HepG2 cells

Methyl mercury (MeHg) is a highly toxic substance and the effect of selenium against MeHg toxicity is a hot topic. Until now, no related works have been reported from the view of the point of elemental speciation which is promising to study the mechanism at the molecular level. In this work, to reveal the effect of selenocystine (SeCys2) against MeHg cytotoxicity in HepG2 cells, a comprehensive analytical platform for speciation study of mercury and selenium in MeHg incubated or MeHg and SeCys2 co-incubated HepG2 cells was developed by integrating liquid chromatography (LC) - inductively coupled plasma mass spectrometry (ICP-MS) hyphenated techniques and chip-based pretreatment method. Interesting phenomenon was found that the co-incubation of MeHg with SeCys2 promoted the uptake of MeHg in HepG2 cells, but reduced the cytotoxicity of MeHg. Results obtained by ICP-MS based hyphenated techniques revealed a possible pathway for the incorporation and excretion of mercury species with the coexistence of SeCys2. The formation of MeHg and SeCys2 aggregation promotes the uptake of MeHg; majority of MeHg transforms into small molecular complexes (MeHg-glutathione (GSH) and MeHg-cysteine (Cys)) in HepG2 cells; and MeHg-GSH is the elimination species which results in reducing the cytotoxicity of MeHg.

Getting the Right Answers for the Right Reasons: Toward Predictive Molecular Simulations of Water with Many-Body Potential Energy Functions.

The central role played by water in fundamental processes relevant to different disciplines, including chemistry, physics, biology, materials science, geology, and climate research, cannot be overemphasized. It is thus not surprising that, since the pioneering work by Stillinger and Rahman, many theoretical and computational studies have attempted to develop a microscopic description of the unique properties of water under different thermodynamic conditions. Consequently, numerous molecular models based on either molecular mechanics or ab initio approaches have been proposed over the years. However, despite continued progress, the correct prediction of the properties of water from small gas-phase clusters to the liquid phase and ice through a single molecular model remains challenging. To large extent, this is due to the difficulties encountered in the accurate modeling of the underlying hydrogen-bond network in which both number and strength of the hydrogen bonds vary continuously as a result of a subtle interplay between energetic, entropic, and nuclear quantum effects. In the past decade, the development of efficient algorithms for correlated electronic structure calculations of small molecular complexes, accompanied by tremendous progress in the analytical representation of multidimensional potential energy surfaces, opened the doors to the design of highly accurate potential energy functions built upon rigorous representations of the many-body expansion (MBE) of the interaction energies. This Account provides a critical overview of the performance of the MB-pol many-body potential energy function through a systematic analysis of energetic, structural, thermodynamic, and dynamical properties as well as of vibrational spectra of water from the gas to the condensed phase. It is shown that MB-pol achieves unprecedented accuracy across all phases of water through a quantitative description of each individual term of the MBE, with a physically correct representation of both short- and long-range many-body contributions. Comparisons with experimental data probing different regions of the water potential energy surface from clusters to bulk demonstrate that MB-pol represents a major step toward the long-sought-after "universal model" capable of accurately describing the molecular properties of water under different conditions and in different environments. Along this path, future challenges include the extension of the many-body scheme adopted by MB-pol to the description of generic solutes as well as the integration of MB-pol in an efficient theoretical and computational framework to model acid-base reactions in aqueous environments. In this context, given the nontraditional form of the MB-pol energy and force expressions, synergistic efforts by theoretical/computational chemists/physicists and computer scientists will be critical for the development of high-performance software for many-body molecular dynamics simulations.

Staying Together: Protein Molecules in Mesoscopic Clusters

Collective behavior of protein molecules in solutions is critically important for understanding their biological functions, as well as for efficient control of various technological processes. A number of recent experimental studies have observed the formation of various clusters in protein solutions in different systems (1–5). While the existence of small molecular complexes in solutions is a common phenomenon, a surprising thing in protein solutions is a variety and complexity of such aggregates.

Renal clearance and degradation of glutathione-coated copper nanoparticles.

Degradation of inorganic nanoparticles (NPs) into small molecular complexes is often observed in the physiological environment; however, how this process influences renal clearance of inorganic NPs is largely unknown. By systematically comparing renal clearance of degradable luminescent glutathione coated copper NPs (GS-CuNPs) and their dissociated products, Cu(II)-glutathione disulfide (GSSG) complexes (Cu(II)-GSSG), we found that GS-CuNPs were eliminated through the urinary system surprisingly faster and accumulated in the liver much less than their smaller dissociation counterparts. With assistance of radiochemistry and positron emission tomography (PET) imaging, we found that the observed "nano size" effect in enhancing renal clearance is attributed to the fact that GS-CuNPs are more resistant to serum protein adsorption than Cu(II)-GSSG. In addition, since dissociation of GS-CuNPs follows zero-order chemical kinetics, their renal clearance and biodistribution also depend on initial injection doses and their dissociation processes. Quantitative understanding of size effect and other factors involved in renal clearance and biodistribution of degradable inorganic NPs will lay down a foundation for further development of renal-clearable inorganic NPs with minimized nanotoxicity.

Understanding molecular crystals with dispersion-inclusive density functional theory: pairwise corrections and beyond.

CONSPECTUS: Molecular crystals are ubiquitous in many areas of science and engineering, including biology and medicine. Until recently, our ability to understand and predict their structure and properties using density functional theory was severely limited by the lack of approximate exchange-correlation functionals able to achieve sufficient accuracy. Here we show that there are many cases where the simple, minimally empirical pairwise correction scheme of Tkatchenko and Scheffler provides a useful prediction of the structure and properties of molecular crystals. After a brief introduction of the approach, we demonstrate its strength through some examples taken from our recent work. First, we show the accuracy of the approach using benchmark data sets of molecular complexes. Then we show its efficacy for structural determination using the hemozoin crystal, a challenging system possessing a wide range of strong and weak binding scenarios. Next, we show that it is equally useful for response properties by considering the elastic constants exhibited by the supramolecular diphenylalanine peptide solid and the infrared signature of water libration movements in brushite. Throughout, we emphasize lessons learned not only for the methodology but also for the chemistry and physics of the crystals in question. We further show that in many other scenarios where the simple pairwise correction scheme is not sufficiently accurate, one can go beyond it by employing a computationally inexpensive many-body dispersive approach that results in useful, quantitative accuracy, even in the presence of significant screening and/or multibody contributions to the dispersive energy. We explain the principles of the many-body approach and demonstrate its accuracy for benchmark data sets of small and large molecular complexes and molecular solids.

G-四链体DNA稳定剂的研究进展

Human telomere consists of a series of DNA sequences rich in Guanine, which may form G-quadruplex structure. The formation and stabilization of the specific structure by small molecular compounds can not only inhibit the telomerase and disrupt the mechanism of the maintenance of telomere in cancer cells but also work as a probe for G-quedruplex on the research of the biological functions of G-quadruplex and diagnosis of relevant diseases. So the designing of stabilizers of G-quadruplex has been one of the focuses of chemical biology in recent years. The G-quadruplex stabilizers can be divided in two types up to now: small organic molecular compounds and metal complexes. This review focuses on the latest progress of the two parts, especially the latter one.

Quantitative analysis of individual hepatocyte growth factor receptor clusters in influenza A virus infected human epithelial cells using localization microscopy

In this report, we applied a special localization microscopy technique (Spectral Precision Distance/Spatial Position Determination Microscopy/SPDM) to quantitatively analyze the effect of influenza A virus (IAV) infection on the spatial distribution of individual HGFR (Hepatocyte Growth Factor Receptor) proteins on the membrane of human epithelial cells at the single molecule resolution level. We applied this SPDM method to Alexa 488 labeled HGFR proteins with two different ligands. The ligands were either HGF (Hepatocyte Growth Factor), or IAV. In addition, the HGFR distribution in a control group of mock-incubated cells without any ligands was investigated. The spatial distribution of 1×106 individual HGFR proteins localized in large regions of interest on membranes of 240 cells was quantitatively analyzed and found to be highly non-random. Between 21% and 24% of the HGFR molecules were located in 44,304 small clusters with an average diameter of 54nm. The mean density of HGFR molecule signals per individual cluster was very similar in control cells, in cells with ligand only, and in IAV infected cells, independent of the incubation time. From the density of HGFR molecule signals in the clusters and the diameter of the clusters, the number of HGFR molecule signals per cluster was estimated to be in the range between 4 and 11 (means 5–6). This suggests that the membrane bound HGFR clusters form small molecular complexes with a maximum diameter of few tens of nm, composed of a relatively low number of HGFR molecules. This article is part of a Special Issue entitled: Viral Membrane Proteins — Channels for Cellular Networking.

Wave function methods for fractional electrons

Determining accurate chemical potentials is of considerable interest in various chemical and physical contexts: from small molecular charge-transfer complexes to bandgap in bulk materials such as semi-conductors. Chemical potentials are typically evaluated either by density functional theory, or, alternatively, by computationally more intensive Greens function based GW computations. To calculate chemical potentials, the ground state energy needs to be defined for fractional charges. We thus explore an extension of wave function theories to fractional charges, and investigate the ionization potential and electron affinity as the derivatives of the energy with respect to the electron number. The ultimate aim is to access the chemical potential of correlated wave function methods without the need of explicitly changing the numbers of electrons, making the approach readily applicable to bulk materials. We find that even though second order perturbation theory reduces the fractional charge error considerably compared to Hartree-Fock and standard density functionals, higher order perturbation theory is more accurate and coupled-cluster approaches are even more robust, provided the electrons are bound at the Hartree-Fock level. The success of post-HF approaches to improve over HF relies on two equally important aspects: the integer values are more accurate and the Coulomb correlation between the fractionally occupied orbital and all others improves the straight line behavior significantly as identified by a correction to Hartree-Fock. Our description of fractional electrons is also applicable to fractional spins, illustrating the ability of coupled-cluster singles and doubles to deal with two degenerate fractionally occupied orbitals, but its inadequacy for three and more fractional spins, which occur, for instance, for spherical atoms and when dissociating double bonds. Our approach explores the realm of typical wave function methods that are applied mostly in molecular chemistry, but become available to the solid state community and offer the advantage of an integrated approach: fundamental gap, relative energies, and optimal geometries can be obtained at the same level.

Adsorption and Solution Properties of Bottle-Brush Polyelectrolyte Complexes: Effect of Molecular Weight and Stoichiometry

Polyelectrolyte complexes (PECs) self-assembled from bottle-brush polyelectrolytes, having a cationic main chain and uncharged side chains, and linear anionic sodium polystyrenesulfonate (NaPSS) have been investigated with emphasis on (i) the charge density and side chain density of the bottle-brush polyelectrolyte, (ii) the molecular weight of NaPSS, and (iii) the charge stoichiometry of the mixture. Light scattering and electrophoretic mobility data demonstrate that small molecular complexes are formed when the PEO45 side chain density is sufficiently high to provide steric stabilization and prevent PEC aggregation. The adsorption of PECs on negatively charged silicon oxynitride was investigated using dual polarization interferometry, and the time evolution of the adsorbed amount and thickness was determined. Cationic, uncharged, and negatively charged complexes all adsorb to negatively charged silicon oxynitride, and maximum adsorption is achieved for positively charged complexes containing small amounts of PSS. The adsorbed amount and the kinetics of adsorption are reduced with increasing PSS content, and for any given stoichiometry with increasing PSS molecular weight. These findings are discussed in terms of the PEC structure and the ability of anionic polyelectrolytes to leave the PECs during adsorption.

Solution-processable iridium complexes for efficient orange-red and white organic light-emitting diodes

Two homoleptic and heteroleptic cyclometalated iridium complexes containing the 2-phenylbenzothiozole derivative as the main ligand, 1 and 2, have been synthesized and characterized as efficient orange-red phosphors. Triarylamine was introduced as an important substituent into the 6-position of the benzothiazole ring to tune the photonic and electronic properties of these complexes. Different from most of small molecular iridium complexes, 1 and 2 are solution-processable and their neat films can be obtained by a spin-coating method. Furthermore, their homogeneously dispersed films in a small molecular matrix, 4,4′-N,N′-dicarbazolebiphenyl (CBP), were successfully prepared by solution method even with low doping levels. Organic light-emitting diodes (OLEDs) were fabricated by solution processing the emitting layer containing 1 and 2 as doped emitters in the CBP host. Efficient orange-red electroluminescence by using 5 wt% 2 as the dopant was realized with a maximum efficiency of 14.49 cd A−1 (7.38 lm W−1 and 8.73%) and Commission Internationale de l'Eclairage (CIE) coordinates of (0.60, 0.40), which are among the highest luminance efficiency ever reported for partially solution-processed red and orange-red OLEDs so far. In addition, two-element white OLEDs were achieved with these orange-red phosphors and the traditional blue emitter by spin coating the emission layer. A maximum luminance efficiency of 8.97 cd A−1 and CIE of (0.33, 0.35) were realized.

Determination of labile inorganic and organic species of Al and Cu in river waters using the diffusive gradients in thin films technique

The diffusive gradients in thin films (DGT) technique, using a diffusive gel or a restrictive gel, was evaluated for the determination of labile inorganic and organic species of Al and Cu in model synthetic solutions and river water samples. Experiments were performed both in situ and in the laboratory. In the solutions containing Al ions, the major labile fraction consisted of inorganic species. The organic complex fractions were mainly kinetically inert. For the model Cu solutions, the most labile fraction consisted of inorganic species; however, significant amounts of labile organic complexes of Cu were also present. A comparison was made between the results obtained using restrictive gel DGT and tangential flow ultrafiltration (TF-UF). The Cu fraction determined by restrictive gel DGT (corresponding to the "free" ions plus the labile fraction of small molecular size complexes) was larger than that determined by TF-UF (corresponding to all small molecular size ions), suggesting that the techniques exhibited different porosities for discrimination of inorganic species. For the river water samples analyzed in the laboratory, less than 45% of the analytes were present in labile forms, with most being organic species. For the in situ measurements, the labile inorganic and organic fractions were larger than those obtained in the laboratory analyses. These differences could have been due to errors incurred during sample collection and storage. All results were consistent with those found using two different methods, namely, solid-phase extraction and the DGT technique employing the apparent diffusion coefficient.