Breengiles7236

An efficient method is described for generating a fragmented, permutationally invariant polynomial basis to fit electronic energies and, if available, gradients for large molecules. The method presented rests on the fragmentation of a large molecule into any number of fragments while maintaining the permutational invariance and uniqueness of the polynomials. The new approach improves on a previous one reported by Qu and Bowman by avoiding repetition of polynomials in the fitting basis set and speeding up gradient evaluations while keeping the accuracy of the PES. The method is demonstrated for CH3-NH-CO-CH3 (N-methylacetamide) and NH2-CH2-COOH (glycine).Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker γ-H2AX after DHODH inhibition is preventable by cotreatment with the pan-caspase inhibitor Z-VAD-FMK. Additional solubility and in vitro metabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.A catalytic sequence for the diastereo- and enantioselective preparation of homoallylic alcohols with an adjacent quaternary (stereo)center is reported. The one-pot process relies on the use of a single (achiral or chiral) iridium complex to catalyze the concomitant isomerization of primary allylic alcohols and homoallylboronates into (chiral) aldehydes and allylboronates, respectively. In the same flask, a chiral Brønsted acid is added next to engage the isomerization products into a stereocontrolled allylboration reaction. Structural variations have been performed on both the allylic alcohols and the homoallylboronates. https://www.selleckchem.com/products/homoharringtonine.html This mild process affords an array of stereochemically congested and complex chiral secondary homoallylic alcohols in high yield, excellent diastereoselectivity, and usually high enantioselectivity.Removal of trace chlorobutane (CB) isomers is highly desired to produce high grade 1-chlorobutane (1-CB) and 2-chlorobutane (2-CB). Here, we report that nonporous adaptive crystals (NACs) of perethylated pillar[5]arene (EtP5) and pillar[6]arene (EtP6) effectively remove trace CB isomers. EtP5 NACs can remove trace 1-CB (2%) from 2-CB to improve its purity from 98.0% to 99.9%, while EtP6 NACs can remove trace 2-CB from 1-CB to improve its purity from 98.0% to 99.9%. The adsorption of trace CB isomers results in the formation of new CB-loaded crystal structures, whose thermostability is higher than their corresponding isomer-loaded structures. This determines the selectivity of NACs toward the trace CB isomers. Reversible transformations between nonporous guest-free and guest-loaded structures make EtP5 and EtP6 highly recyclable.The Burkholderia cepacia complex is a group of closely related bacterial species with large genomes that infect immunocompromised individuals and those living with cystic fibrosis. link2 Some of these species are found more frequently and cause more severe disease than others, yet metabolomic differences between these have not been described. Furthermore, our understanding of how these species respond to antibiotics is limited. We investigated the metabolomics differences between three most prevalent Burkholderia spp. associated with cystic fibrosis B. cenocepacia, B. multivorans, and B. dolosa in the presence and absence of the antibiotic trimethoprim. Using a combination of supervised and unsupervised metabolomics data visualization and analysis tools, we describe the overall differences between strains of the same species and between species. Specifically, we report, for the first time, the role of the pyomelanin pathway in the metabolism of trimethoprim. We also report differences in the detection of known secondary metabolites such as fragin, ornibactin, and N-acylhomoserine lactones and their analogs in closely related strains. Furthermore, we highlight the potential for the discovery of new secondary metabolites in clinical strains of Burkholderia spp. The metabolomics differences described in this study highlight the personalized nature of closely related Burkholderia strains.The search for alternatives to bioaccumulative perfluoroalkyl acids (PFAAs) is ongoing. New, still highly fluorinated alternatives are produced in hopes of reducing bioaccumulation. To better estimate this bioaccumulative behavior, we performed dialysis experiments and determined membrane/water partition coefficients, Kmem/w, of six perfluoroalkyl carboxylic acids (PFCAs), three perfluoroalkanesulfonic acids, and four alternatives. We also investigated how passive permeation might influence the uptake kinetics into cells, measuring the passive anionic membrane permeability Pion through planar lipid bilayers for six PFAAs and three alternatives. Experimental Kmem/w and Pion were both predicted well by the COSMO-RS theory (log RMSE 0.61 and 0.46, respectively). link3 Kmem/w values were consistent with the literature data, and alternatives showed similar sorption behavior as PFAAs. Experimental Pion values were high enough to explain observed cellular uptake by passive diffusion with no need to postulate the existence of active uptake processes. However, predicted pKa and neutral permeabilities suggest that also the permeation of the neutral species should be significant in case of PFCAs. This can have direct consequences on the steady-state distribution of PFAAs across cell membranes and thus toxicity. Consequently, we propose a model to predict pH-dependent baseline toxicity based on Kmem/w, which considers the permeation of both neutral and anionic species.Nanoscale membrane curvature is now understood to play an active role in essential cellular processes such as endocytosis, exocytosis, and actin dynamics. Previous studies have shown that membrane curvature can directly affect protein function and intracellular signaling. However, few methods are able to precisely manipulate membrane curvature in live cells. Here, we report the development of a new method of generating nanoscale membrane curvature in live cells that is controllable, reversible, and capable of precise spatial and temporal manipulation. For this purpose, we make use of Bin/Amphiphysin/Rvs (BAR) domain proteins, a family of well-studied membrane-remodeling and membrane-sculpting proteins. Specifically, we engineered two optogenetic systems, opto-FBAR and opto-IBAR, that allow light-inducible formation of positive and negative membrane curvature, respectively. Using opto-FBAR, blue light activation results in the formation of tubular membrane invaginations (positive curvature), controllable down to the subcellular level. Using opto-IBAR, blue light illumination results in the formation of membrane protrusions or filopodia (negative curvature). These systems present a novel approach for light-inducible manipulation of nanoscale membrane curvature in live cells.The molecular origins of Alzheimer's disease are associated with the aggregation of the amyloid-β peptide (Aβ). This process is controlled by a com-plex cellular homeostasis system, which involves a variety of components, including proteins, metabo-lites and lipids. It has been shown in particular that certain components of lipid membranes can speed up Aβ aggregation. This observation prompts the question of whether there are protective cellular mechanisms to counterbalance this effect. Here, to address this issue, we investigate the role of the composition of lipid membranes in modulating the aggregation process of Aβ. By adopting a chemical kinetics approach, we first identify a panel of lipids that affect the aggregation of the 42-residues form of Aβ (Aβ42), ranging from enhancement to inhibi-tion. We then show that these effects tend to aver-age out in mixtures of these lipids, as such mixtures buffer extreme aggregation behaviors as the num-ber of components increases. These results indicate that a degree of quality control on protein aggrega-tion can be achieved through a mechanism by which an increase in the molecular complexity of lipid membranes balances opposite effects and cre-ates resilience to aggregation.Growing interest in molten salts as effective high-temperature heat-transfer fluids for sustainable energy systems drives a critical need to fundamentally understand the interactions between metals and molten salts. This work utilizes the multimodal microscopy methods of synchrotron X-ray nanotomography and electron microscopy to investigate the 3D morphological and chemical evolution of two-model systems, pure nickel metal and Ni-20Cr binary alloy, in a representative molten salt (KCl-MgCl2 50-50 mol %, 800 °C). In both systems, unexpected shell-like structures formed because of the presence of more noble tungsten, suggesting a potential route of using Ni-W alloys for enhanced molten-salt corrosion resistance. The binary alloy Ni-20Cr developed a bicontinuous porous structure, reassembling functional porous metals manufactured by dealloying. This work elucidates better mechanistic understanding of corrosion in molten salts, which can contribute to the design of more reliable alloys for molten salt applications including next-generation nuclear and solar power plants and opens the possibility of using molten salts to fabricate functional porous materials.This work combines a machine learning potential energy function with a modular enhanced sampling scheme to obtain statistically converged thermodynamical properties of flexible medium-size organic molecules at high ab initio level. We offer a modular environment in the python package MORESIM that allows custom design of replica exchange simulations with any level of theory including ML-based potentials. Our specific combination of Hamiltonian and reservoir replica exchange is shown to be a powerful technique to accelerate enhanced sampling simulations and explore free energy landscapes with a quantum chemical accuracy unattainable otherwise (e.g., DLPNO-CCSD(T)/CBS quality). This engine is used to demonstrate the relevance of accessing the ab initio free energy landscapes of molecules whose stability is determined by a subtle interplay between variations in the underlying potential energy and conformational entropy (i.e., a bridged asymmetrically polarized dithiacyclophane and a widely used organocatalyst) both in the gas phase and in solution (implicit solvent).The need for detailed structural characterization of glycerophospholipids (GPLs) for many types of biologically motivated applications has led to the development of novel mass spectrometry-based methodologies that utilize alternative ion activation methods. Ultraviolet photodissociation (UVPD) has shown great utility for localizing sites of unsaturation within acyl chains and to date has predominantly been used for positive mode analysis of GPLs. In the present work, UVPD is used to localize sites of unsaturation in GPL anions. Similar to UVPD mass spectra of GPL cations, UVPD of deprotonated or formate-adducted GPLs yields diagnostic fragment ions spaced 24 Da apart. This method was integrated into a liquid chromatography workflow and used to evaluate profiles of sites of unsaturation of lipids in Escherichia coli (E. coli) and Acinetobacter baumannii (A. baumannii). When assigning sites of unsaturation, E. coli was found to contain all unsaturation elements at the same position relative to the terminal methyl carbon of the acyl chain; the first carbon participating in a site of unsaturation was consistently seven carbons along the acyl chain when counting carbons from the terminal methyl carbon.