Variety Of Small Organic Molecules Research Articles

The effect of methyl group rotation on 1H-1H solid-state NMR spin-diffusion spectra.

Fast magic-angle spinning (MAS) NMR experiments open the way for proton-detected NMR studies and have been explored in the past years for a broad range of materials, comprising biomolecules and pharmaceuticals. Proton-spin diffusion (SD) is a versatile polarization-transfer mechanism and plays an important role in resonance assignment and structure determination. Recently, the occurrence of negative cross peaks in 2D 1H-1H SD-based spectra has been reported and explained with higher-order SD effects, in which the chemical shifts of the involved quadruple of nuclei need to compensate each other. We herein report negative cross peaks in SD-based spectra observed for a variety of small organic molecules involving methyl groups. We combine experimental observations with numerical and analytical simulations to demonstrate that the methyl groups can give rise to coherent (SD) as well as incoherent (Nuclear Overhauser Enhancement, NOE) effects, both in principle manifesting themselves as negative cross peaks in the 2D spectra. Analytical calculations and simulations however show that higher-order coherent contributions dominate the experimentally observed negative peaks in our systems. Methyl groups are prone to the observation of such higher order coherent effects. Due to their low-frequency shifted 1H resonances, the chemical-shift separation relative to for instance aromatic protons in spatial proximity is substantial (>4.7 ppm in the studied examples) preventing any sizeable second-order spin-diffusion processes, which would mask the negative contribution to the peaks.

Improved order and transport in C60 thin films grown on SiO2 via use of transient templates

The performance of C60 semiconducting films is linked to the degree of crystallinity and ordering, properties that strongly depend on the substrate, and growth conditions. Substrate–molecule interactions can be specifically tailored by employing growth templates to achieve a desired thin film structure. However, the presence of a growth template after the film deposition is usually not desirable as it may change the properties of the layer of interest. The ability to remove a growth template without any disruption to the active layer would be highly beneficial. A simple method of template removal by annealing is presented here. A variety of small organic molecules (perfluoropentacene, [6]phenacene, and α-sexithiophene) were used as a growth template to obtain a high-quality well-ordered C60 thin film. In situ grazing-incidence wide-angle x-ray scattering was employed to study the structural changes of C60 thin films during template removal. While a slight disturbance of the thin film structure was observed during template removal caused by evaporated molecules from the growth template escaping through the C60 layer, the disruption is only temporary. When the annealing process is concluded, only the well-ordered C60 thin film directly on top of SiO2 is left, which is not achievable without the use of a growth template. Improved crystallinity and grain size of such a thin film, when compared to preparation without a growth template, lead to a significant improvement of the charge carrier mobility. Importantly, template removal prevents the formation of undesired ambipolar transistor characteristics.

Description of Potential Energy Surfaces of Molecules Using FFLUX Machine Learning Models.

A new type of model, FFLUX, to describe the interaction between atoms has been developed as an alternative to traditional force fields. FFLUX models are constructed by applying the kriging machine learning method to the topological energy partitioning method, interacting quantum atoms (IQA). The effect of varying parameters in the construction of the FFLUX models is analyzed, with the most dominant effects found to be the structure of the molecule and the number of conformations used to build the model. Using these models, the optimization of a variety of small organic molecules is performed, with sub kJ mol-1 accuracy in the energy of the optimized molecules. The FFLUX models are also evaluated in terms of their performance in describing the potential energy surfaces (PESs) associated with specific degrees of freedoms within molecules. While the accurate description of PESs presents greater challenges than individual minima, FFLUX models are able to achieve errors of <2.5 kJ mol-1 across the full C-C-C-C dihedral PES of n-butane, indicating the future possibilities of the technique.

Thermodynamics of Concanavalin A Self-Association in the Presence of Osmolytes

Protein-protein interactions are critical for biological function and depend significantly on environmental factors. A wide variety of small organic molecules that comprise the cellular environment are capable of interacting with proteins to affect folding, binding, and association. The plant lectin concanavalin A (ConA) undergoes a reversible, pH dependent dimer-to-tetramer equilibrium and has been used in our laboratory as a model system to study the effect of osmolytes on protein self-association. Previous research determined that trimethylamine N-oxide (TMAO) stabilizes the tetrameric conformation, while urea favors the dimer. Studying the equilibrium over a range of temperatures allowed quantification of the enthalpy change (∆H) and entropy change (∆S) of tetramer formation. Urea increased both the ∆H and ∆S of tetramer formation, while TMAO decreased both. These effects are consistent with preferential hydration of the dimer-dimer interface in TMAO solution and preferential binding of urea to the interface. KEYWORDS: Concanavalin A; Osmolytes; Trimethylamine N-oxide; Urea; Protein-Protein Interaction; Equilibrium; Enthalpy; Preferential Hydration

Molecular composition and heterogeneity of the LRRC8-containing swelling-activated osmolyte channels in primary rat astrocytes.

The volume-regulated anion channel (VRAC) is a swelling-activated chloride channel that is permeable to inorganic anions and a variety of small organic molecules. VRAC is formed via heteromerization of LRRC8 proteins, among which LRRC8A is essential, while LRRC8B/C/D/E serve as exchangeable complementary partners. We used an RNAi approach and radiotracer assays to explore which LRRC8 isoforms contribute to swelling-activated release of diverse organic osmolytes in rat astrocytes. Efflux of uncharged osmolytes (myo-inositol and taurine) was suppressed by deletion of LRRC8A or LRRC8D, but not by deletion of LRRC8C+LRRC8E. Conversely, release of charged osmolytes (d-aspartate) was strongly reduced by deletion of LRRC8A or LRRC8C+LRRC8E, but largely unaffected by downregulation of LRRC8D. Our findings point to the existence of multiple heteromeric VRACs in the same cell type: LRRC8A/D-containing heteromers appear to dominate release of uncharged osmolytes, while LRRC8A/C/E, with the additional contribution of LRRC8D, creates a conduit for movement of charged molecules. The volume-regulated anion channel (VRAC) is the ubiquitously expressed vertebrate Cl- /anion channel that is composed of proteins belonging to the LRRC8 family and activated by cell swelling. In the brain, VRAC contributes to physiological and pathological release of a variety of small organic molecules, including the amino acid neurotransmitters glutamate, aspartate and taurine. In the present work, we explored the role of all five LRRC8 family members in the release of organic osmolytes from primary rat astrocytes. Expression of LRRC8 proteins was modified using an RNAi approach, and amino acid fluxes via VRAC were quantified by radiotracer assays in cells challenged with hypoosmotic medium (30% reduction in osmolarity). Consistent with our prior work, knockdown of LRRC8A potently and equally suppressed the release of radiolabelled d-[14 C]aspartate and [3 H]taurine. Among other LRRC8 subunits, downregulation of LRRC8D strongly inhibited release of the uncharged osmolytes [3 H]taurine and myo-[3 H]inositol, without major impact on the simultaneously measured efflux of the charged d-[14 C]aspartate. In contrast, the release of d-[14 C]aspartate was preferentially sensitive to deletion of LRRC8C+LRRC8E, but unaffected by downregulation of LRRC8D. Finally, siRNA knockdown of LRRC8C+LRRC8D strongly inhibited the release of all osmolytes. Overall, our findings suggest the existence of at least two distinct heteromeric VRACs in astroglial cells. The LRRC8A/D-containing permeability pathway appears to dominate the release of uncharged osmolytes, while an alternative channel (or channels) is composed of LRRC8A/C/D/E and responsible for the loss of charged molecules.

Focused grid-based resampling for protein docking and mapping.

The fast Fourier transform (FFT) sampling algorithm has been used with success in application to protein-protein docking and for protein mapping, the latter docking a variety of small organic molecules for the identification of binding hot spots on the target protein. Here we explore the local rather than global usage of the FFT sampling approach in docking applications. If the global FFT based search yields a near-native cluster of docked structures for a protein complex, then focused resampling of the cluster generally leads to a substantial increase in the number of conformations close to the native structure. In protein mapping, focused resampling of the selected hot spot regions generally reveals further hot spots that, while not as strong as the primary hot spots, also contribute to ligand binding. The detection of additional ligand binding regions is shown by the improved overlap between hot spots and bound ligands.

The activation effect of hainantoxin-I, a peptide toxin from the Chinese spider, Ornithoctonus hainana, on intermediate-conductance Ca2+-activated K+ channels.

Intermediate-conductance Ca2+-activated K+ (IK) channels are calcium/calmodulin-regulated voltage-independent K+ channels. Activation of IK currents is important in vessel and respiratory tissues, rendering the channels potential drug targets. A variety of small organic molecules have been synthesized and found to be potent activators of IK channels. However, the poor selectivity of these molecules limits their therapeutic value. Venom-derived peptides usually block their targets with high specificity. Therefore, we searched for novel peptide activators of IK channels by testing a series of toxins from spiders. Using electrophysiological experiments, we identified hainantoxin-I (HNTX-I) as an IK-channel activator. HNTX-I has little effect on voltage-gated Na+ and Ca2+ channels from rat dorsal root ganglion neurons and on the heterologous expression of voltage-gated rapidly activating delayed rectifier K+ channels (human ether-à-go-go-related gene; human ERG) in HEK293T cells. Only 35.2% ± 0.4% of the currents were activated in SK channels, and there was no effect on BK channels. We demonstrated that HNTX-I was not a phrenic nerve conduction blocker or acutely toxic. This is believed to be the first report of a peptide activator effect on IK channels. Our study suggests that the activity and selectivity of HNTX-I on IK channels make HNTX-I a promising template for designing new drugs for cardiovascular diseases.

Synthesis and Small Molecule Exchange Studies of a Magnesium Bisformate Metal–Organic Framework: An Experiment in Host–Guest Chemistry for the Undergraduate Laboratory

Experiments are described that introduce students to the important concepts of host–guest chemistry and size exclusion in porous metal–organic frameworks (MOFs). The experiment has been successfully carried out in both introductory and advanced-level inorganic chemistry laboratories. Students synthesized the porous MOF, α-Mg3(O2CH)6, and examined its ability to take up a variety of small organic molecules into its pores using 1H NMR spectroscopy. The MOF exhibited size exclusion and students rationalized this behavior based on the structures of the organic molecules and the pore size of the MOF.

Temperature controlled dip-pen nanolithography

Dip-pen nanolithography (DPN) has emerged as a powerful tool for creatingsophisticated micron- and nanoscale features of various molecules, such as small organicmolecules, on a variety of substrates. Despite significant advances in recent years, theinfluence of temperature on molecular transport for nanostructure fabrication has notbeen fully explored. Herein, it is shown how the dimensions of patterned organicnanostructures can be controlled by using a cooling/heating module. This method allowsnanometer-sized feature fabrication of a variety of small organic molecules, including‘inks’ that have been deemed very difficult to write under ambient conditions.Features with dimensions as small as 30 nm have been successfully reproducedusing the newly developed temperature control device in conjunction with DPN.

Fragment-based identification of druggable ‘hot spots’ of proteins using Fourier domain correlation techniques

The binding sites of proteins generally contain smaller regions that provide major contributions to the binding free energy and hence are the prime targets in drug design. Screening libraries of fragment-sized compounds by NMR or X-ray crystallography demonstrates that such 'hot spot' regions bind a large variety of small organic molecules, and that a relatively high 'hit rate' is predictive of target sites that are likely to bind drug-like ligands with high affinity. Our goal is to determine the 'hot spots' computationally rather than experimentally. We have developed the FTMAP algorithm that performs global search of the entire protein surface for regions that bind a number of small organic probe molecules. The search is based on the extremely efficient fast Fourier transform (FFT) correlation approach which can sample billions of probe positions on dense translational and rotational grids, but can use only sums of correlation functions for scoring and hence is generally restricted to very simple energy expressions. The novelty of FTMAP is that we were able to incorporate and represent on grids a detailed energy expression, resulting in a very accurate identification of low-energy probe clusters. Overlapping clusters of different probes are defined as consensus sites (CSs). We show that the largest CS is generally located at the most important subsite of the protein binding site, and the nearby smaller CSs identify other important subsites. Mapping results are presented for elastase whose structure has been solved in aqueous solutions of eight organic solvents, and we show that FTMAP provides very similar information. The second application is to renin, a long-standing pharmaceutical target for the treatment of hypertension, and we show that the major CSs trace out the shape of the first approved renin inhibitor, aliskiren. FTMAP is available as a server at http://ftmap.bu.edu/.

DYNAMIC DETERMINANTS OF THE CYTOADHERENCE OF PLASMODIUM FALCIPARUM–INFECTED ERYTHROCYTES

thologists also observed that the process was not uniform among the vital organs, noting particularly the “accumulation in the cerebral vessels of red blood corpuscles loaded with amoebae.” The result of this pathologic process was described as “mechanical alterations in the circulation”; or, in other words, a traffic jam. With the development of methods for ex vivo culture of Plasmodium falciparum, malariologists have studied this process of cytoadherence of parasitized erythrocytes to endothelial cells (or the purified immobilized cell surface “receptors”) in the laboratory and have progressively tried to recreate the same conditions that occur in vivo. This is not easy, as blood is a thick and complex soup of deformable cells suspended in a variable consomme of plasma proteins, electrolytes, and a variety of small organic molecules. Its effective viscosity changes nonlinearly under the different shear rates encountered in the circulation (non-Newtonian behavior). Malaria is associated with fever, progressive anemia, thrombocytopenia, an increase in acute phase proteins, reduction in serum albumin, and, in severe infections, re

The Drosophila ninaG Oxidoreductase Acts in Visual Pigment Chromophore Production

The Drosophila ninaG mutant is characterized by low levels of Rh1 rhodopsin, because of the inability to transport this rhodopsin from the endoplasmic reticulum to the rhabdomere. ninaG mutants do not affect the biogenesis of the minor opsins Rh4 and Rh6. A genetic analysis placed the ninaG gene within the 86E4-86E6 chromosomal region. A sequence analysis of the 15 open reading frames within this region from the ninaG(P330) mutant allele identified a stop codon in the CG6728 gene. Germ-line transformation of the CG6728 genomic region rescued the ninaG mutant phenotypes, confirming that CG6728 corresponds to the ninaG gene. The NinaG protein belongs to the glucose-methanol-choline oxidoreductase family of flavin adenine dinucleotide-binding enzymes catalyzing hydroxylation and oxidation of a variety of small organic molecules. High performance liquid chromatography analysis of retinoids was used to gain insight into the in vivo role of the NinaG oxidoreductase. The results show that when Rh1 is expressed as the major rhodopsin, ninaG flies fail to accumulate 3-hydroxyretinal. Further, in transgenic flies expressing Rh4 as the major rhodopsin, 3-hydroxyretinal is the major retinoid in ninaG+, but a different retinoid profile is observed in ninaG(P330). These results indicate that the ninaG oxidoreductase acts in the biochemical pathway responsible for conversion of retinal to the rhodopsin chromophore, 3-hydroxyretinal.

An application of the QM-QSAR method to predict and rationalize lipophilicity of simple monomers

The goal of this study is to develop a model used to predict octanol/water partition coefficients (log P(o/w)) values for a variety of potential dental materials. In this way, a primary consideration for potential toxicity and a rough estimate of solubility in various environments can be obtained. The AM1 semiempirical quantum mechanical method (in AMPAC) was used to compute chemical data for all compounds in the study. CODESSA then imported the chemical information from AMPAC and computed a large set of informational descriptors. A quantitative structure activity relationship (QSAR) model was derived correlating experimental results from a training set of molecules with certain of the descriptors computed above. A training set of 92 molecules was used to derive the QSAR model and three descriptors were obtained: the molecular surface area, the total dipole moment of the molecule, and FPSA-3 (fractional atom charge weighted partial positive surface area). Various quality indicators were also computed and all fell within acceptable ranges: R(2)=0.945; adjusted R(2)=0.943; R(cv)(2)=0.940; variance inflation factors (VIF) for the descriptors above are 1.116, 1.044, and 1.162, respectively. This QSAR model can be used to accurately and rapidly predict log P(o/w) values for a wide variety of small organic molecules, including potential dental monomers.

Rapid estimation of octanol–water partition coefficients using synthesized vesicles in electrokinetic chromatography

Vesicle electrokinetic chromatography (VEKC) using vesicles synthesized from the oppositely charged surfactants cetyltrimethylammonium bromide (CTAB) and sodium octyl sulfate (SOS) and from the double-chained anionic surfactant bis(2-ethylhexyl)sodium sulfosuccinate (AOT) was applied to the indirect measurement of octanol–water partition coefficients (log P o/w). A variety of small organic molecules with varying functional groups, pesticides, and organic acids were evaluated by correlating log P o/w and the logarithm of the retention factor (log k′) and comparing the calibrations. A linear solvation energy relationship (LSER) analysis was conducted to describe the retention behavior of the vesicle systems and compared to that of octanol–water partitioning. The solute hydrogen bond donating behavior is slightly different with the vesicle interactions using CTAB–SOS vesicles as compared to the octanol–water partitioning model. The AOT vesicle and octanol–water partitioning systems showed similar partitioning characteristics. VEKC provides rapid separations for determinations of log P o/w in the range of 0.5 to 5 using CTAB–SOS vesicles and 0 to 5.5 using AOT vesicles.

Adsorption to Ice of n-Alcohols (Ethanol to 1-Hexanol), Acetic Acid, and Hexanal

The gas-to-ice uptakes of a variety of small organic molecules (C2 to C6 n-alcohols, acetic acid and hexanal) have been measured in a coated-wall flow tube coupled to an electron-impact mass spectrometer. The ice films are prepared by freezing liquid water and the temperature range covered is between 213 and 245 K. With the exceptions of 1-hexanol and high partial pressures of 1-pentanol, the surface coverages at 228 K are adequately described by a standard Langmuir adsorption isotherm model consistent with a saturated surface coverage of 2 to 3 × 1014 molecules/cm2, where the area is the geometric surface area of the film. For similar partial pressures, 1-hexanol exhibits very much larger uptakes than the other species, an indication that multilayer adsorption is occurring. The equilibrium constant for the partitioning between the gas-phase organic and its adsorbed form has been measured from the linear dependence of the surface coverage on pressure at low partial pressures. The temperature dependence of...

Stochastic Sensing with Protein Pores

Biosensors are required in a wide variety of applications for which existing technologies are inadequate. Recently, sensor elements with favorable properties have been made by engineering transmembrane protein pores. Analyte molecules modulate the ionic current passing through the engineered pores under a transmembrane potential. Stochastic sensing, which uses currents from single pores, is an especially attractive prospect. This approach yields both the concentration and identity of an analyte, the latter from its distinctive current signature. In one example, the bacterial pore-forming protein staphylococcal α-hemolysin (αHL) has been altered to permit the detection of divalent metal cations by using mutagenesis to place a cation binding site within the conductive pathway. In a second example, the hemolysin pore has been modified with cyclodextrins, which act as non-covalent molecular adapters, to allow the detection of a variety of small organic molecules. The great promise and wide applicability of stochastic sensing warrants efforts aimed at the development of a practicable device.

Stochastic Sensing with Protein Pores

Biosensors are required in a wide variety of applications for which existing technologies are inadequate. Recently, sensor elements with favorable properties have been made by engineering transmembrane protein pores. Analyte molecules modulate the ionic current passing through the engineered pores under a transmembrane potential. Stochastic sensing, which uses currents from single pores, is an especially attractive prospect. This approach yields both the concentration and identity of an analyte, the latter from its distinctive current signature. In one example, the bacterial pore-forming protein staphylococcal α-hemolysin (αHL) has been altered to permit the detection of divalent metal cations by using mutagenesis to place a cation binding site within the conductive pathway. In a second example, the hemolysin pore has been modified with cyclodextrins, which act as non-covalent molecular adapters, to allow the detection of a variety of small organic molecules. The great promise and wide applicability of stochastic sensing warrants efforts aimed at the development of a practicable device.

In Vitro Selected Oligonucleotides as Tools in Organic Chemistry

DNA and RNA molecules have been isolated from synthetic combinatorial libraries that are able to bind a variety of small organic molecules and catalyze different chemical reactions. The properties of these molecules as well as the techniques for their identification are discussed with respect to potential applications in

Bond‐Forming Initiation in Spontaneous Addition and Polymerization Reactions of Alkenes

AbstractSpontaneous addition and polymerization reactions of alkenes of different electron‐densities result in a wide variety of small organic molecules and high polymers. Tetramethylenes are proposed as key intermediates, i.e. resonance hybrids of 1,4‐diradical and zwitterionic limiting structures. Their character is determined by the substituents at the terminals: Zwitterionic character is favored by strong donors, such as alkoxy and dialkylamino groups, at the carbenium center and strong acceptor group such as diesters and cyano‐esters, at the acceptor end, and aryl and vinyl groups as donors. Zwitterionic tetramethylenes initiate ionic homopolymerization, while diradical tetramethylenes initiate alternating copolymerization, thus providing an extremely sensitive technique for the detection and characterization of these intermediates. The effects of the donor and acceptor substituents can be arranged as an “Organic Chemist's Periodic Table”, wherein the areas of mechanistic change clearly emerge and which provides predictive capability.—This unifying concept of bondforming initiation is extended to spontaneous addition and polymerization reactions of heteroatom acceptor molecules and 7,7,8,8‐tetrasubstituted quinodimethanes and of compounds possessing labile σ‐bonds, such as halogens and peroxides. Radical‐ion pairs, charge‐transfer complexes and adventitious impurities are excluded as significant initiators.

Organic Analysis of the Returned Lunar Sample

Lunar fines have been examined for organic compounds by crushing, programmed heating, hydrofluoric acid etching, and solvent extraction. Products were examined by mass spectroscopy. A variety of small organic molecules, including methane and other hydrocarbons, accompanied the release of the rare gases when the sample was heated in a stepwise fashion to 900 degrees C under vacuum. Methane is more abundant (abundance on the order of 1 part per million) than argon in the matrix-entrapped gases liberated by hydrofluoric acid etching of lunar fines. Methane is also present in a dark portion of the gas-rich meteorite Kapoeta.