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At least 163 records · Page 9

Exploring the Impact of Active Site Structure on the Conversion of Methane to Methanol in Cu‐Exchanged Zeolites

Abstract In the past, Cu‐oxo or ‐hydroxy clusters hosted in zeolites have been suggested to enable the selective conversion of methane to methanol, but the impact of the active site's stoichiometry and structure on methanol production is still poorly understood. Herein, we apply theoretical modeling in conjunction with experiments to study the impact of these two factors on partial methane oxidation in the Cu‐exchanged zeolite SSZ‐13. Phase diagrams developed from first‐principles suggest that Cu‐hydroxy or Cu‐oxo dimers are stabilized when O 2 or N 2 O are used to activate the catalyst, respectively. We confirm these predictions experimentally and determine that in a stepwise conversion process, Cu‐oxo dimers can convert twice as much methane to methanol compared to Cu‐hydroxyl dimers. Our theoretical models rationalize how Cu‐di‐oxo dimers can convert up to two methane molecules to methanol, while Cu‐di‐hydroxyl dimers can convert only one methane molecule to methanol per catalytic cycle. These findings imply that in Cu clusters, at least one oxo group or two hydroxyl groups are needed to convert one methane molecule to methanol per cycle. This simple structure–activity relationship allows to intuitively understand the potential of small oxygenated or hydroxylated transition metal clusters to convert methane to methanol.

Chemistry↗

Low-temperature oxidation of methane and methanol on iridium oxides

Iridium oxides (IrO 2 ) are of significant interest for low-temperature oxidation of small molecules such as CH 4 and CH 3 OH, although the physical origin of their high activity remains under debate. Here, we demonstrate that the enhanced activity of IrO 2 arises from the formation of coordinatively unsaturated (CUS) oxygen species. By combining ambient-pressure X-ray spectroscopy and density functional theory calculations, we present evidence for the formation of CUS oxygen during CH 4 and CH 3 OH oxidation. Such surface speciation correlates with the conversion of methane to carbon dioxide and methanol to methyl formate on rutile IrO 2 and hydrous IrO 2 powder catalysts in a plug-flow reactor at room temperature. These findings extend the understanding of the physical origin of the higher activity of iridium oxide thin-film catalysts to powder catalysts and provide insights into the tuneability of iridium-oxide-containing catalysts for low-temperature C–H and O–H bond activation.

AP-XPS↗

Omics-Based Comparison of Fungal Virulence Genes, Biosynthetic Gene Clusters, and Small Molecules in Penicillium expansum and Penicillium chrysogenum

Penicillium expansum is a ubiquitous pathogenic fungus that causes blue mold decay of apple fruit postharvest, and another member of the genus, Penicillium chrysogenum, is a well-studied saprophyte valued for antibiotic and small molecule production. While these two fungi have been investigated individually, a recent discovery revealed that P. chrysogenum can block P. expansum-mediated decay of apple fruit. To shed light on this observation, we conducted a comparative genomic, transcriptomic, and metabolomic study of two P. chrysogenum (404 and 413) and two P. expansum (Pe21 and R19) isolates. Global transcriptional and metabolomic outputs were disparate between the species, nearly identical for P. chrysogenum isolates, and different between P. expansum isolates. Further, the two P. chrysogenum genomes revealed secondary metabolite gene clusters that varied widely from P. expansum. This included the absence of an intact patulin gene cluster in P. chrysogenum, which corroborates the metabolomic data regarding its inability to produce patulin. Additionally, a core subset of P. expansum virulence gene homologues were identified in P. chrysogenum and were similarly transcriptionally regulated in vitro. Molecules with varying biological activities, and phytohormone-like compounds were detected for the first time in P. expansum while antibiotics like penicillin G and other biologically active molecules were discovered in P. chrysogenum culture supernatants. Our findings provide a solid omics-based foundation of small molecule production in these two fungal species with implications in postharvest context and expand the current knowledge of the Penicillium-derived chemical repertoire for broader fundamental and practical applications.

Bartholomew, Holly P. (ORCID:0000000292726399)↗

Near-complete depolymerization of polyesters with nano-dispersed enzymes

Successfully interfacing enzymes and biomachinery with polymers affords on-demand modification and/or programmable degradation during the manufacture, utilization and disposal of plastics, but requires controlled biocatalysis in solid matrices with macromolecular substrates. Embedding enzyme microparticles speeds up polyester degradation, but compromises host properties and unintentionally accelerates the formation of microplastics with partial polymer degradation. Here we show that by nanoscopically dispersing enzymes with deep active sites, semi-crystalline polyesters can be degraded primarily via chain-end-mediated processive depolymerization with programmable latency and material integrity, akin to polyadenylation-induced messenger RNA decay. It is also feasible to achieve processivity with enzymes that have surface-exposed active sites by engineering enzyme-protectant-polymer complexes. Poly(caprolactone) and poly(lactic acid) containing less than 2 weight per cent enzymes are depolymerized in days, with up to 98 per cent polymer-to-small-molecule conversion in standard soil composts and household tap water, completely eliminating current needs to separate and landfill their products in compost facilities. Furthermore, oxidases embedded in polyolefins retain their activities. However, hydrocarbon polymers do not closely associate with enzymes, as their polyester counterparts do, and the reactive radicals that are generated cannot chemically modify the macromolecular host. This study provides molecular guidance towards enzyme-polymer pairing and the selection of enzyme protectants to modulate substrate selectivity and optimize biocatalytic pathways. Furthermore, the results also highlight the need for in-depth research in solid-state enzymology, especially in multi-step enzymatic cascades, to tackle chemically dormant substrates without creating secondary environmental contamination and/or biosafety concerns.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Blocking C-terminal processing of KRAS4b via a direct covalent attack on the CaaX-box cysteine

RAS is the most frequently mutated oncogene in cancer. RAS proteins show high sequence similarities in their G-domains but are significantly different in their C-terminal hypervariable regions (HVR). These regions interact with the cell membrane via lipid anchors that result from posttranslational modifications (PTM) of cysteine residues. KRAS4b is unique as it has only one cysteine that undergoes PTM, C185. Small molecule covalent modification of C185 would block any form of prenylation and subsequently inhibit attachment of KRAS4b to the cell membrane, blocking its biological activity. We translated this concept to the discovery and development of disulfide tethering screen hits into irreversible covalent modifiers of C185. These compounds inhibited proliferation of KRAS4b-driven mouse embryonic fibroblasts, but not cells driven by N-myristoylated KRAS4b that harbor a C185S mutation and are not dependent on C185 prenylation. Top–down proteomics was used to confirm target engagement in cells. These compounds bind in a pocket formed when the HVR folds back between helix 3 and 4 in the G-domain (HVR-α3-α4). This interaction can happen in the absence of small molecules as predicted by molecular dynamics simulations and is stabilized in the presence of C185 binders as confirmed by small-angle X-ray scattering and solution NMR. NOESY-HSQC, an NMR approach that measures internuclear distances of 6 Å or less, and structure analysis identified the critical residues and interactions that define the HVR-α3-α4 pocket. Further development of compounds that bind to this pocket could be the basis of a new approach to targeting KRAS cancers.

C185↗

A Top-Down Strategy to Engineer ActiveLayer Morphology for Highly Efficient and Stable All-Polymer Solar Cells

A major challenge hindering the further development of all-polymer solar cells (all-PSCs) employing polymerized small-molecule acceptors is the relatively low fill factor (FF) due to the difficulty in controlling the active-layer morphology. The issues typically arise from oversized phase separation resulting from the thermodynamically unfavorable mixing between two macromolecular species, and disordered molecular orientation/packing of highly anisotropic polymer chains. Herein, a facile top-down controlling strategy to engineer the morphology of all-polymer blends is developed by leveraging the layer-by-layer (LBL) deposition. Optimal intermixing of polymer components can be achieved in the two-step process by tuning the bottom-layer polymer swelling during top-layer deposition. Consequently, both the molecular orientation/packing of the bottom layer and the molecular ordering of the top layer can be optimized with a suitable top-layer processing solvent. A favorable morphology with gradient vertical composition distribution for efficient charge transport and extraction is therefore realized, affording a high all-PSC efficiency of 17.0% with a FF of 76.1%. The derived devices also possess excellent long-term thermal stability and can retain >90% of their initial efficiencies after being annealed at 65 °C for 1300 h. In conclusion, these results validate the distinct advantages of employing an LBL processing protocol to fabricate high-performance all-PSCs.

14 SOLAR ENERGY↗

Novel small molecule inhibitor of Kpnβ1 induces cell cycle arrest and apoptosis in cancer cells

Karyopherin beta 1 (Kpnβ1) is a major nuclear import receptor that mediates the import of cellular cargoes into the nucleus. Recently it has been shown that Kpnβ1 is highly expressed in several cancers, and its inhibition by siRNA induces apoptotic cancer cell death, while having little effect on non-cancer cells. This study investigated the effect of a novel small molecule, Inhibitor of Nuclear Import-60 (INI-60), on cancer cell biology, as well as nuclear import activities associated with Kpnβ1, and cancer progression in vivo using cervical and oesophageal cancer cell lines. INI-60 treatment resulted in the inhibition of cancer cell proliferation, colony formation, migration and invasion, and induced a G1/S cell cycle arrest, followed by cancer cell death via apoptosis. Non-cancer cells were minimally affected by INI-60 at concentrations that inhibited cancer cells. INI-60 treatment altered the localisation of Kpnβ1 and its cargoes, NFκB/p65, NFAT and AP-1, and the overexpression of Kpnβ1 reduced INI-60 cytotoxicity. INI-60 also inhibited KYSE 30 oesophageal cancer cell line growth in vivo. Taken together, these results show that INI-60 inhibits the nuclear import of Kpnβ1 cargoes and interferes with cancer cell biology. INI-60 presents as a potential therapeutic approach for cancers of different tissue origins and warrants further investigation as a novel anti-cancer agent.

60 APPLIED LIFE SCIENCES↗

Superatoms as Superior Catalysts: ZrO versus Pd

Abstract Single‐atom catalysts are the focus of studies for over a decade due to their enhanced reactivity at smaller sizes. However, they have limitations as they offer only one active site, which may not be sufficient for reactions requiring the co‐adsorption of multiple reactants. Additionally, atoms can migrate on a substrate and coalesce, resulting in decreased reactivity. Here, an alternate path, a single‐superatom catalyst is provided. Superatoms are clusters of atoms that mimic the chemistry of atoms even if they do not contain a single atom whose chemistry they mimic. Motivated by an experimental paper on the photoelectron‐spectroscopy of negatively charged ions where ZrO is found to mimic properties of a Pd atom, first the reaction of Pd and ZrO with small molecules in the gas‐phase is studied and found that ZrO not only mimics the chemistry of Pd, but is able to activate these molecules more strongly than Pd. A detailed first‐principles study of CO 2 reduction (CO 2 ‐RR) and hydrogen evolution reactions (HER) on Pd and ZrO supported on graphene, Au(111), and Cu(111) surfaces shows that superatoms are indeed superior catalysts. The ability to design numerous superatoms by varying size and composition offers a promising new paradigm for catalyst design and synthesis.

Chemistry↗

Enzymatic Nitrogen Incorporation Using Hydroxylamine

Hydroxylamine-derived reagents have enabled versatile nitrene transfer reactions for introducing nitrogen-containing functionalities in small-molecule catalysis as well as biocatalysis. These reagents, however, result in poor atom economy and stoichiometric organic waste. Activating hydroxylamine (NH 2 OH) for nitrene transfer offers a low-cost and sustainable route to amine synthesis, since water is the sole byproduct. Despite its presence in nature, however, hydroxylamine is not known to be used for enzymatic nitrogen incorporation in biosynthesis. Here, we report an engineered heme enzyme that can utilize hydroxylammonium chloride, an inexpensive commodity chemical, for nitrene transfer. Directed evolution of Pyrobaculum arsenaticum protoglobin generated efficient enzymes for benzylic C–H primary amination and styrene aminohydroxylation. Mechanistic studies supported a stepwise radical pathway involving rate-limiting hydrogen atom transfer. Furthermore, this unprecedented activity is a useful addition to the ‘nitrene transferase’ repertoire and hints at possible future discovery of natural enzymes that use hydroxylamine for amination chemistry.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca 2+ , 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca 2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca 2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dt max , an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that β-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

59 BASIC BIOLOGICAL SCIENCES↗

Small-molecule allosteric inhibitors of GPX4

Here, encouraged by the dependence of drug-resistant, metastatic cancers on GPX4, we examined biophysical mechanisms of GPX4 inhibition, which revealed an unexpected allosteric site. We found that this site was involved in native regeneration of GPX4 under low glutathione conditions. Covalent binding of inhibitors to this allosteric site caused a conformational change, inhibition of activity, and subsequent cellular GPX4 protein degradation. To verify this site in an unbiased manner, we screened a library of compounds and identified and validated that an additional compound can covalently bind in this allosteric site, inhibiting and degrading GPX4. We determined co-crystal structures of six different inhibitors bound in this site. We have thus identified an allosteric mechanism for small molecules targeting aggressive cancers dependent on GPX4.

59 BASIC BIOLOGICAL SCIENCES↗

Pose Classification Using Three-Dimensional Atomic Structure-Based Neural Networks Applied to Ion Channel–Ligand Docking

The identification of promising lead compounds showing pharmacological activities toward a biological target is essential in early stage drug discovery. With the recent increase in available small-molecule databases, virtual high-throughput screening using physics-based molecular docking has emerged as an essential tool in assisting fast and cost-efficient lead discovery and optimization. However, the best scored docking poses are often suboptimal, resulting in incorrect screening and chemical property calculation. We address the pose classification problem by leveraging data-driven machine learning approaches to identify correct docking poses from AutoDock Vina and Glide screens. To enable effective classification of docking poses, we present two convolutional neural network approaches: a three-dimensional convolutional neural network (3D-CNN) and an attention-based point cloud network (PCN) trained on the PDBbind refined set. We demonstrate the effectiveness of our proposed classifiers on multiple evaluation data sets including the standard PDBbind CASF-2016 benchmark data set and various compound libraries with structurally different protein targets including an ion channel data set extracted from Protein Data Bank (PDB) and an in-house KCa3.1 inhibitor data set. Our experiments show that excluding false positive docking poses using the proposed classifiers improves virtual high-throughput screening to identify novel molecules against each target protein compared to the initial screen based on the docking scores.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Solvent influence on non-adiabatic interfacial electron transfer at conductive oxide electrolyte interfaces

The kinetics for interfacial electron transfer (ET) from a transparent conductive oxide (tin-doped indium oxide, ITO, Sn:In 2 O 3 ) to molecular acceptors 4-[N,N-di(p-tolyl)amino]benzylphosphonic acid, TPA, and [Ru II (bpy) 2 (4,4' -(PO 3 H 2 ) 2 -bpy)] 2+ , RuP, positioned at variable distances within and beyond the electric double layer (EDL), were quantified in benzonitrile and methanol by nanosecond absorption spectroscopy as a function of the thermodynamic driving force, -ΔG ° . Relevant ET parameters such as the rate constant, k et , reorganization energy, λ, and electronic coupling, Hab, were extracted from the kinetic data. Overall, k et increased as the distance between the molecular acceptor and the conductor decreased. For redox active molecules within the Helmholtz planes of the EDL, k et was nearly independent of -ΔG° , consistent with a negligibly small λ value. Rips–Jortner analysis revealed a non-adiabatic electron transfer mechanism consistent with H ab < 1 cm -1 . The data indicate that the barrier for electron transfer is greatly diminished at the conductor–electrolyte interface.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

RTx-303, an Orally Bioavailable Polθ Polymerase Inhibitor That Potentiates PARP Inhibitors in BRCA Mutant Tumors

Abstract DNA polymerase θ (Polθ) is a polymerase-helicase fusion protein that is synthetically lethal with homologous recombination (HR) factors, such as BRCA1/2, and confers resistance to PARP inhibitors (PARPi) and other genotoxic cancer therapies. Previously developed Polθ polymerase (Polθ-pol) inhibitors (Polθi) exhibited limited pharmacological activity and metabolic stability, warranting the development of a Polθi with improved drug-like properties. Here, we developed RTx-303, a selective allosteric small-molecule Polθ-pol inhibitor that exhibits 5.1 nM IC50, 88% oral bioavailability, and a prolonged half-life along with its equipotent metabolite. X-ray crystallography highlights the development of a solvent-exposed side-chain that is essential for the optimal drug-like properties of RTx-303. Notably, RTx-303 exhibits significantly higher cellular potency than previously developed Polθ-pol inhibitors and strongly potentiates PARPi in BRCA1/2 mutant cells and patient-derived xenograft models. The superior potency, robust pharmacological activity, and high tolerability of RTx-303 warrant further development as a Polθ-pol inhibitor drug candidate.

Chandramouly, Gurushankar [Thomas Jefferson Univer↗

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

60 APPLIED LIFE SCIENCES↗

Direct tests of cytochrome c and c 1 functions in the electron transport chain of malaria parasites

The mitochondrial electron transport chain (ETC) of Plasmodium malaria parasites is a major antimalarial drug target, but critical cytochrome (cyt) functions remain unstudied and enigmatic. Parasites express two distinct cyt c homologs (c and c-2) with unusually sparse sequence identity and uncertain fitness contributions. P. falciparum cyt c-2 is the most divergent eukaryotic cyt c homolog currently known and has sequence features predicted to be incompatible with canonical ETC function. We tagged both cyt c homologs and the related cyt c1 for inducible knockdown. Translational repression of cyt c and cyt c1 was lethal to parasites, which died from ETC dysfunction and impaired ubiquinone recycling. In contrast, cyt c-2 knockdown or knockout had little impact on blood-stage growth, indicating that parasites rely fully on the more conserved cyt c for ETC function. Biochemical and structural studies revealed that both cyt c and c-2 are hemylated by holocytochrome c synthase, but UV-vis absorbance and EPR spectra strongly suggest that cyt c-2 has an unusually open active site in which heme is stably coordinated by only a single axial amino acid ligand and can bind exogenous small molecules. These studies provide a direct dissection of cytochrome functions in the ETC of malaria parasites and identify a highly divergent Plasmodium cytochrome c with molecular adaptations that defy a conserved role in eukaryotic evolution.

60 APPLIED LIFE SCIENCES↗

Tuning the Redox Activity of Metal–Organic Frameworks for Enhanced, Selective O 2 Binding: Design Rules and Ambient Temperature O 2 Chemisorption in a Cobalt–Triazolate Framework

Metal–organic frameworks (MOFs) with coordinatively unsaturated metal sites are appealing as adsorbent materials due to their tunable functionality and ability to selectively bind small molecules. Through the use of computational screening methods based on periodic density functional theory, we investigate O 2 and N 2 adsorption at the coordinatively unsaturated metal sites of several MOF families. A variety of design handles are identified that can be used to modify the redox activity of the metal centers, including changing the functionalization of the linkers (replacing oxido donors with sulfido donors), anion exchange of bridging ligands (considering μ-Br – , μ-Cl – , μ-F – , μ-SH – , or μ-OH – groups), and altering the formal oxidation state of the metal. As a result, we show that it is possible to tune the O 2 affinity at the open metal sites of MOFs for applications involving the strong and/or selective binding of O 2 . In contrast with O 2 adsorption, N 2 adsorption at open metal sites is predicted to be relatively weak across the MOF dataset, with the exception of MOFs containing synthetically elusive V 2+ open metal sites. As one example from the screening study, we predicted that exchanging the μ-Cl – ligands of M 2 Cl 2 (BBTA) (H 2 BBTA = 1H,5H-benzo(1,2-d:4,5-d')bistriazole) with μ-OH – groups would significantly enhance the strength of O 2 adsorption at the open metal sites without a corresponding increase in the N 2 affinity. Experimental investigation of Co 2 Cl 2 (BBTA) and Co 2 (OH) 2 (BBTA) confirms that the former exhibits weak physisorption of both N 2 and O 2 , whereas the latter is capable of chemisorbing O 2 at room temperature in a highly selective manner. The O 2 chemisorption behavior is attributed to the greater electron-donating character of the μ-OH – ligands and the presence of H-bonding interactions between the μ-OH – bridging ligands and the reduced O 2 adsorbate.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Eliminating the Burn‐in Loss of Efficiency in Organic Solar Cells by Applying Dimer Acceptors as Supramolecular Stabilizers

Abstract The meta‐stable active layer morphology of organic solar cells (OSCs) is identified as the main cause of the rapid burn‐in loss of power conversion efficiency (PCE) during long‐term device operation. However, effective strategies to eliminate the associated loss mechanisms from the initial stage of device operation are still lacking, especially for high‐efficiency material systems. Herein, the introduction of molecularly engineered dimer acceptors with adjustable thermal transition properties into the active layer of OSCs to serve as supramolecular stabilizers for regulating the thermal transitions and optimizing the crystallization of the absorber composites is reported. By establishing intimate π‐π interactions with small‐molecule acceptors, these stabilizers can effectively reduce the trap‐state density (N t ) in the devices to achieve excellent PCEs over 19%. More importantly, the lowN t associated with an initially optimized morphology can be maintained under external stresses to significantly reduce the PCE burn‐in loss in devices. This research reveals a judicious approach to improving OPV stability by establishing a comprehensive correlation between material properties, active‐layer morphology, and device performance, for developing burn‐in‐free OSCs.

Chemistry↗