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At least 451 records · Page 25

Combinatorial optimization and spatial remodeling of CYPs to control product profile

Activating inert substrates is a challenge in nature and synthetic chemistry, but essential for creating functionally active molecules. In this work, we used a combinatorial optimization approach to assemble cytochrome P450 monooxygenases (CYPs) and reductases (CPRs) to achieve a target product profile. By creating 110 CYP-CPR pairs and iteratively screening different pairing libraries, we demonstrated a framework for establishing a CYP network that catalyzes six oxidation reactions at three different positions of a chemical scaffold. Target product titer was improved by remodeling endoplasmic reticulum (ER) size and spatially controlling the CYPs’ configuration on the ER. Out of 47 potential products that could be synthesized, 86% of the products synthesized by the optimized network was our target compound quillaic acid (QA), the aglycone backbone of many pharmaceutically important saponins, and fermentation achieved QA titer 2.23 g/L.

59 BASIC BIOLOGICAL SCIENCES↗

Thick Electrode Design for Facile Electron and Ion Transport: Architectures, Advanced Characterization, and Modeling

The demand for lithium ion batteries continues to expand for powering applications such as portable electronics, grid-scale energy storage, and electric vehicles. As the application requirements advance, the innovation of lithium ion batteries toward higher energy density and power output is required. Along with the investigation of new materials, an important strategy for increasing battery energy content is to design electrodes with high areal loading to minimize the fraction of nonactive materials such as current collectors, separators, and packaging components, resulting in significant gains in energy content and the reduction of the system-level cost. However, the adoption of thick high areal loading electrodes has been impeded by sluggish charge transport and mechanical instability. With conventional slurry cast electrodes, battery function significantly deteriorates with increases in electrode thickness due to high cell polarization and the incomplete utilization of active materials. Thus, a consideration of approaches that facilitate an understanding and eventual adoption of high-loading electrodes is warranted to enable the deliberate advancement of next-generation batteries. Herein, this Account considers three aspects critical to the science and technology of thick high-loading electrodes. The first discussion covers recent approaches to the design and fabrication of high-loading electrodes. Ensuring electrical contact throughout the electrode is accomplished through the manipulation of conductive additives or using a conductive scaffold within the electrode. Ion transport can be facilitated through electrode design and fabrication approaches that deliberately control the electrode porosity and tortuosity. Second, advanced characterization methodologies are presented as the ability to determine the origins of transport limitations provide the insight needed to deliberately approach future designs. Spectroscopic and diffraction methods have been used to characterize the 2D and 3D pore structure and composition of the electrodes. Furthermore, operando methods that yield spatially and temporally resolved information regarding the progression of the electrochemical reaction are highlighted. The third aspect considered is the utilization of modeling. Physically based continuum models linked with the results of experimental characterization have been demonstrated and then allow the rapid simulation of a variety of deliberate electrode designs and their impacts on functional electrochemistry. Variables relevant to the designs can be tested by the model under a series of use conditions to identify those of most promise for a specific application. Finally, an outlook on future opportunities for high-loading battery electrode research is provided to inform and entice practitioners in the field to pursue these important directions of inquiry.

25 ENERGY STORAGE↗

Charge Transport in Zirconium-Based Metal–Organic Frameworks

Metal–organic frameworks (MOFs) are a class of crystalline porous materials characterized by inorganic nodes and multitopic organic linkers. Because of their molecular-scale porosity and periodic intraframework chemical functionality, MOFs are attractive scaffolds for supporting and/or organizing catalysts, photocatalysts, chemical-sensing elements, small enzymes, and numerous other functional-property-imparting, nanometer-scale objects. Notably, these objects can be installed after the synthesis of the MOF, eliminating the need for chemical and thermal compatibility of the objects with the synthesis milieu. Thus, postsynthetically functionalized MOFs can present three-dimensional arrays of high-density, yet well-separated, active sites. Depending on the application and corresponding morphological requirements, MOF materials can be prepared in thin-film form, pelletized form, isolated single-crystal form, polycrystalline powder form, mixed-matrix membrane form, or other forms. For certain applications, most obviously catalytic hydrolysis and electro- or photocatalytic water splitting, but also many others, an additional requirement is water stability. MOFs featuring hexa-zirconium(IV)-oxy nodes satisfy this requirement. For applications involving electrocatalysis, charge storage, photoelectrochemical energy conversion, and chemiresistive sensing, a further requirement is electrical conductivity, as embodied in electron or hole transport. As most MOFs, under most conditions, are electrically insulating, imparting controllable charge-transport behavior is both a chemically intriguing and chemically compelling challenge. Herein, we describe three strategies to render zirconium-based metal–organic frameworks (MOFs) tunably electrically conductive and, therefore, capable of transporting charge on the few nanometers (i.e., several molecular units) to few micrometers (i.e., typical dimensions for MOF microcrystallites) scale. The first strategy centers on redox-hopping between periodically arranged, chemically equivalent sites, essentially repetitive electron (or hole) self-exchange. Zirconium nodes are electrically insulating, but they can function as grafting sites for (a) redox-active inorganic clusters or (b) molecular redox couples. Alternatively, charge hopping based on linker redox properties can be exploited. Marcus’s theory of electron transfer has proven useful for understanding/predicting trends in redox-hopping based conductivity, most notably, in accounting for variations as great as 3000-fold depending on the direction of charge propagation through structurally anisotropic MOFs. In MOF environments, propagation of electronic charge via redox hopping is necessarily accompanied by movement of charge-compensating ions. Consequently, rates of redox hopping can depend on both the identity and concentration of ions permeating the MOF. In the context of electrocatalysis, an important goal is to transport electronic charge fast enough to match or exceed the inherent activity of MOF-based or MOF-immobilized catalysts. Bandlike electronic conductivity is the focus of an alternative strategy: one based on the introduction of molecular guests capable of forming donor–acceptor charge transfer complexes with the host framework. Theory again can be applied predictively to alter conductivity. A third strategy similarly emphasizes electronic conductivity, but it makes use of added bridges in the form of molecular oligomers or inorganic clusters that can then be linked to span the length of a MOF crystallite. For all strategies, retention of molecular-scale porosity is emphasized, as this property is key to many applications. Lastly, while our focus is on Zr-MOFs, the described approaches clearly are extendable to other MOF compositions, as has already been demonstrated, in part, in studies by others.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Programming Amphiphilic Peptoid Oligomers for Hierarchical Assembly and Inorganic Crystallization

Natural organisms make a wide variety of exquisitely complex, nano-, micro-, and macroscale structured materials in an energy-efficient and highly reproducible manner. During these processes, the information-carrying biomolecules (e.g., proteins, peptides, and carbohydrates) enable (1) hierarchical organization to assemble scaffold materials and execute high-level functions and (2) exquisite control over inorganic materials synthesis, generating biominerals whose properties are optimized for their functions. Inspired by nature, significant efforts have been devoted to developing functional materials that can rival those natural molecules by mimicking in vivo functions using engineered proteins, peptides, DNAs, sequence-defined synthetic molecules (e.g., peptoids), and other biomimetic polymers. Among them, peptoids, a new type of synthetic mimetics of peptides and proteins, have received particular attention because they combine the merits of both synthetic polymers (e.g., high chemical stability and efficient synthesis) and biomolecules (e.g., sequence programmability and biocompatibility). The lack of both chirality and hydrogen bonds in their backbone results in a highly designable peptoid-based system with reduced structural complexity and side chain-chemistry-dominated properties. Here in this Account, we present our recent efforts in this field by programming amphiphilic peptoid sequences for (1) the controlled self-assembly into different hierarchically structured nanomaterials with favorable properties and (2) manipulating inorganic (nano)crystal nucleation, growth, and assembly into superstructures. First, we designed a series of amphiphilic peptoids with controlled side chain chemistries that self-assembled into 1D highly stiff and dynamic nanotubes, 2D membrane-mimetic nanosheets, hexagonally patterned nanoribbons, and 3D nanoflowers. These crystalline nanostructures exhibited sequence-dependent properties and showed promise for different applications. The corresponding peptoid self-assembly pathways and mechanisms were also investigated by leveraging in situ atomic force microscopy studies and molecular dynamics simulations, which showed precise sequence dependency. Second, inspired by peptide- and protein-controlled formation of hierarchical inorganic nanostructures in nature, we developed peptoid-based biomimetic approaches for controlled synthesis of inorganic materials (e.g., noble metals and calcite), in which we took advantage of the substantial side chain chemistry of peptoids and investigated the relationship between the peptoid sequences and the morphology and growth kinetics of inorganic materials. For example, to overcome the challenges (e.g., complexity of protein- and peptide-folding, poor thermal and chemical stabilities) facing the area of protein- and peptide-controlled synthesis of inorganic materials, we recently reported the design of sequence-defined peptoids for controlled synthesis of highly branched plasmonic gold particles. Moreover, we developed a rule of thumb for designing peptoids that predictively enabled the morphological evolution from spherical to coral-shaped gold nanoparticles (NPs). With this Account, we hope to stimulate the research interest of chemists and materials scientists and promote the predictive synthesis of functional and robust materials through the design of sequence-defined synthetic molecules.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Engineering Nanostructured Interfaces of Hexagonal Boron Nitride-Based Materials for Enhanced Catalysis

Hexagonal boron nitrides (h-BNs) are attractive two-dimensional (2D) nanomaterials that consist of alternating B and N atoms and layered honeycomb-like structures similar to graphene. They have exhibited unique properties and promising application potentials in the field of energy storage and transformation. Recent advances in utilizing h-BN as a metal-free catalyst in the oxidative dehydrogenation of propane have triggered broad interests in exploring h-BN in catalysis. However, h-BN-based materials as robust nanocatalysts in heterogeneous catalysis are still underexplored because of the limited methodologies capable of affording h-BN with controllable crystallinity, abundant porosity, high purity, and defect engineering, which played important roles in tuning their catalytic performance. Here, in this account, our recent progress in addressing the above issues will be highlighted, including the synthesis of high-quality h-BN-based nanomaterials via both bottom-up and top-down pathways and their catalytic utilization as metal-free catalysts or as supports to tune the interfacial electronic properties on the metal nanoparticles (NPs). First, we will focus on the large-scale fabrication of h-BN nanosheets (h-BNNSs) with high crystallinity, improved surface area, satisfactory purity, and tunable defects. h-BN derived from the traditional approaches using boron trioxide and urea as the starting materials generally contains carbon/oxygen impurities and has low crystallinity. Several new strategies were developed to address the issues. Using bulk h-BN as the precursor via gas exfoliation in liquid nitrogen, single- or few-layered h-BNNS with abundant defects could be generated. Amorphous h-BN precursors could be converted to h-BN nanosheets with high crystallinity assisted by a magnesium metallic flux via a successive dissolution/precipitation/crystallization procedure. The as-fabricated h-BNNS featured high crystallinity and purity as well as abundant porosity. An ionothermal metathesis procedure was developed using inorganic molten salts (NaNH 2 and NaBH 4 ) as the precursors. The h-BN scaffolds could be produced on a large scale with high yield, and the as-afforded materials possessed high purity and crystallinity. Second, utilization of the as-prepared h-BN library as metal-free catalysts in dehydrogenation and hydrogenation reactions will be summarized, in which they exhibited enhanced catalytic activity over the counterparts from the previous synthesis method. Third, the interface modulation between metal NPs with the as-prepared defects’ abundant h-BN support will be highlighted. The h-BN-based strong metal–support interaction (SMSI) nanocatalysts were constructed without involving reducible metal oxides via the ionothermal procedure we developed by deploying specific inorganic metal salts, acting as robust nanocatalysts in CO oxidation. Under conditions simulated for practical exhaust systems, promising catalytic efficiency together with high thermal stability and sintering resistance was achieved. Across all of these examples, unique insights into structures, defects, and interfaces that emerge from in-depth characterization through microscopy, spectroscopy, and diffraction will be highlighted.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Enhancement of Uranium Ionization Efficiencies Using Zn-MOF-74 Derived Nanoporous Ion Emitters for Thermal Ionization Mass Spectrometry

The recent introduction of nano-porous ion emitters (nano-PIEs) formed from metal organic frameworks (MOFs) has demonstrated the potential to enhance sensitivity for thermal ionization mass spectrometry (TIMS). Nano-PIEs take advantage of the parent MOF’s chemical and structural tunability to form scaffolds for ion emitters. A study by Barpaga et al. 2023 on MOF-74 as the parent material found that with high volatility metals in their framework uranium sample utilization efficiency (SUE) increases by up to nine-fold (e.g., Zn-MOF-74) compared to that of the analyte on a bare filament (~0.05%). Here, in this study, we investigate the performance of Zn-MOF-74 to maximize uranium efficiencies at the trace level (= 10 -12 g) by altering the parent MOF morphology and chemistry (i.e., MOF crystal sizes and thermal degradation) and optimizing its integration with TIMS (i.e., MOF mass on a filament and ramp conditions). We observed improvement in SUE up to 20 times (≤1.0%) that of a bare filament load when nano-PIEs derived from nanocrystals of Zn-MOF-74 were heated under a specific current ramp condition. This demonstrates that rates of nano-PIE structural collapse during TIMS analysis and the subsequently formed nanomaterials (and their features) can be tuned to control analyte ionization.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Controlling Drug Absorption, Release, and Erosion of Photopatterned Protein Engineered Hydrogels

A protein-engineered triblock copolymer hydrogel composed of two self-assembling domains (SADs) has been fabricated by a photoactivatable diazirine group followed by ultraviolet (UV)-mediated crosslinking. The photocrosslinkable protein polymer CEC-D has been patterned into various features including different micrometer-scale stripes by using lithographic techniques. The patterned hydrogels are important for encapsulation of small molecules where a photopatterned fraction of 50% is optimal for maximum absorption. Stripe-patterned CEC-D 100–100 exhibits slightly lower swelling ratios, an 8.9 times lower erosion profile, and a 2.6-fold higher drug release compared to the unpatterned hydrogel control, CEC-D0. Our studies demonstrate the potential of photocrosslinkable protein polymer hydrogels to be used as scaffolds for therapeutic delivery of small molecules. Furthermore, through photolithographic techniques on the protein hydrogel, a variety of functionalities can be achieved by patterning different features enabling the mimicry of biological systems.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

Three-Dimensional Printable, Extremely Soft, Stretchable, and Reversible Elastomers from Molecular Architecture-Directed Assembly

3D printing elastomers enables the fabrication of many technologically important structures and devices such as tissue scaffolds, sensors, actuators, and soft robots. However, conventional 3D printable elastomers are intrinsically stiff; moreover, the process of printing often requires external mechanical support and/or post-treatment. In this work, we exploit the self-assembly of a responsive linear-bottlebrush-linear triblock copolymer to create stimuli-reversible, extremely soft, and stretchable elastomers and demonstrate their applicability as inks for in situ direct-write printing 3D structures without the aid of external mechanical support or post-treatment. By developing a procedure for controlled synthesis of such architecturally designed block copolymers, we create elastomers with extensibility up to 600% and Young’s moduli down to ~10 2 Pa, 10 6 times softer than plastics and more than 102 times softer than all existing 3D printable elastomers. Moreover, the elastomers are thermostable and remain to be solid up to 180 °C, yet they are 100% solvent-reprocessable. Their extreme softness, stretchability, thermostability, and solvent-reprocessability bode well for future applications.

36 MATERIALS SCIENCE↗

Role of Metal Selection in the Radiation Stability of Isostructural M-UiO-66 Metal–Organic Frameworks

Robust and versatile metal–organic frameworks (MOFs) have emerged as sophisticated scaffolds to meet the critical needs of the nuclear community, but their performance depends on their underexplored structural integrities in high- radiation fields. The contributions of selected metal nodes in the radiation stability of MOFs within the isostructural M-UiO-66 series (where M = Zr, Ce, Hf, Th, and Pu; Zr-UiO-66 experiments were executed in a previous work) have been determined. Ce-, Hf-, and Th-UiO-66 MOF samples were irradiated via gamma and He-ion methodologies to obtain doses up to 3 MGy and 85 MGy, respectively, the latter strikingly higher than that obtained in most other studies. Appreciable self-irradiation constituted the total absorbed doses, up to 31 MGy of the gamma-irradiated Pu-UiO-66 samples. Structural degradation was ascertained by powder X-ray diffraction, X-ray total scattering, vibrational spectroscopy, and, where possible, N 2 physisorption isotherms. Diffuse reflectance infrared Fourier transform spectroscopy provided atomic-level mechanistic insights to reveal that the node-linker connection was most susceptible to radiation damage. Density functional theory calculations were performed on cluster models to evaluate the binding energy of the linkers to each metal node. Here, while the isostructures disclosed the same breakdown signatures, distinct radiation sensitivity as a function of metal selection was evident and followed the trend Hf-UiO-66 ~ Zr-UiO-66 > Th-UiO-66 > Pu-UiO-66 > Ce-UiO-66. We anticipate that these endeavors will contribute to the rational design of radiation-resistant materials for targeted applications.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Engineered Living Materials For Sustainability

Recent advances in synthetic biology and materials science have given rise to a new form of materials, namely engineered living materials (ELMs), which are composed of living matter or cell communities embedded in self-regenerating matrices of their own or artificial scaffolds. Like natural materials such as bone, wood, and skin, ELMs, which possess the functional capabilities of living organisms, can grow, self-organize, and self-repair when needed. They also spontaneously perform programmed biological functions upon sensing external cues. Currently, ELMs show promise for green energy production, bioremediation, disease treatment, and fabricating advanced smart materials. This review first introduces the dynamic features of natural living systems and their potential for developing novel materials. We then summarize the recent research progress on living materials and emerging design strategies from both synthetic biology and materials science perspectives. Lastly, we discuss the positive impacts of living materials on promoting sustainability and key future research directions.

36 MATERIALS SCIENCE↗

Metal–Organic Frameworks as Catalysts for (De)Hydrogenation: Progress, Challenges, and Perspectives

Storing hydrogen through chemical bonding in liquid-organic hydrogen carriers (LOHCs) offers a safer and more practical approach for hydrogen transportation compared to physical liquefaction, which is limited by low volumetric efficiency and gas release. The efficiency of LOHC systems is highly dependent on effective catalysts, which are typically composed of transition metals supported on metal oxides. However, these materials often rely upon costly noble metals, and their nonuniform nature limits mechanistic insights and structure–function relationships that could improve catalyst design. Metal–organic frameworks (MOFs) are promising alternatives to existing catalysts due to their crystalline, tunable, and porous nature. However, their use as catalysts for (de)hydrogenation reactions remains largely underexplored. Related to this, we identify two general classes of MOFs reported as catalysts for (de)hydrogenation reactions: MOFs as scaffolds for catalytically active species and MOFs that function as reactive materials themselves. MOF composites anchor reactive nanoparticles or homogeneous species, imparting reactivity to the framework. The confinement effects experienced by the affixed species, combined with favorable substrate adsorption interactions or acid sites provided by the MOF, enhance the stability, selectivity, and activity of these catalysts for (de)hydrogenation reactions. Additionally, catalytically active MOFs often feature open metal sites at the node or undergo postsynthetic modification at either node or linker to impart reactivity. Here, taking inspiration from these materials, we outline the current state and key challenges of utilizing MOFs as (de)hydrogenation catalysts and propose research pathways to advance materials in this field for energy applications.

Catalysts↗

An Easily Prepared Monomeric Cobalt(II) Tetrapyrrole Complex That Efficiently Promotes the 4e – /4H + Peractivation of O 2 to Water

The selective 4e – /4H + reduction of dioxygen to water is an important reaction that takes place at the cathode of fuel cells. Monomeric aromatic tetrapyrroles (such as porphyrins, phthalocyanines, and corroles) coordinated to Co(II) or Co(III) have been considered as oxygen reduction catalysts due to their low cost and relative ease of synthesis. Furthermore, these systems have been repeatedly shown to be selective for O 2 reduction by the less desired 2e – /2H + pathway to yield hydrogen peroxide. Herein, we report the initial synthesis and study of a Co(II) tetrapyrrole complex based on a nonaromatic isocorrole scaffold that is competent for 4e – /4H + oxygen reduction reaction (ORR). This Co(II) 10,10-dimethyl isocorrole (Co[10-DMIC]) is obtained in just four simple steps and has excellent yield from a known dipyrromethane synthon. Evaluation of the steady state spectroscopic and redox properties of Co[10-DMIC] against those of Co porphyrin (cobalt 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin, [Co(TPFPP)]) and corrole (cobalt 5,10,15-tris(pentafluorophenyl)corrole triphenylphosphine, Co[TPFPC](PPh 3 )) homologues demonstrated that the spectroscopic and electrochemical properties of the isocorrole are distinct from those displayed by more traditional aromatic tetrapyrroles. Further, the investigation of the ORR activity of Co[10-DMIC] using a combination of electrochemical and chemical reduction studies revealed that this simple, unadorned monomeric Co(II) tetrapyrrole is ~85% selective for the 4e – /4H + reduction of O 2 to H 2 O over the more kinetically facile 2e – /2H + process that delivers H 2 O 2 . In contrast, the same ORR evaluations conducted for the Co porphyrin and corrole homologues demonstrated that these traditional aromatic systems catalyze the 2e – /2H + conversion of O 2 to H 2 O 2 with near complete selectivity. Despite being a simple, easily prepared, monomeric tetrapyrrole platform, Co[10-DMIC] supports an ORR catalysis that has historically only been achieved using elaborate porphyrinoid-based architectures that incorporate pendant proton-transfer groups or ditopic molecular clefts or that impose cofacially oriented O 2 binding sites. Accordingly, Co[10-DMIC] represents the first simple, unadorned, monomeric metalloisocorrole complex that can be easily prepared and shows a privileged performance for the 4e – /4H + peractivation of O 2 to water as compared to other simple cobalt containing tetrapyrroles.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Back to Basics: Lanthanide and Heavy Actinide Chelation at High pH by Niobium Polyoxometalates

Niobium polyoxometalates (Nb-POMs) form in alkaline media, which limits their use as ligands for acidic cations, particularly lanthanides and actinides. Metal-Nb-POM moieties have the potential for emergent and enhanced properties, based on strong complexation behavior and high stability of the resultant materials. Here, in this study, we probe interactions of lanthanides (Pr 3+ , Nd 3+ , Sm 3+ , Eu 3+ , Tb 3+ , Dy 3+ ) and actinides (Am 3+ , Cm 3+ ) with a Nb-POM [Nb 6 O 19 ] 8– (Nb 6 ) in alkaline media. Nb 6 , the most charge-dense Nb-POM, enhances f-element luminescence emission by up to × 10 6 , via Nb-POM-mediated sensitization. Lengthened emission lifetimes correlate with the release of the metal-cation hydration sphere, replaced by multidentate Nb-POMs. The Nb 6 –Ln(An) complexes resist carbonate and phosphate displacement, and Nb 6 –Ln(An) complexation is retained upon isolation of the solids from solution. Electrospray ionization mass spectrometry (ESI-MS) and Raman spectroscopy both indicate the formation of the unprecedented Peacock–Weakley Nb-POM ([LnIII(Nb 5 O 18 ) 2 ] 19- ) in addition to simple Nb 6 –Ln coordination complexes. Luminescence emission spectra support the presence of simple Nb 6 –Ln coordination complexes. Small-angle X-ray scattering (SAXS) evidence the formation of Ln-Nb-POM aggregates. This foundational investigation highlights the potential of Nb-POMs as metal–ligands at basic pH, with value-added properties including scaffolding extended materials and controlling light absorption and emission.

organic↗

Modeling Molecules under Pressure with Gaussian Potentials

The computational modeling of molecules under high pressure is a growing research area that augments experimental high-pressure chemistry. Here, a new electronic structure method for modeling atoms and molecules under pressure, Gaussians On Surface Tesserae Simulate HYdrostatic Pressure (GOSTSHYP) approach, is introduced. In this method, a set of Gaussian potentials is distributed evenly on the van der Waals surface of the investigated chemical system, leading to a compression of the electron density and the atomic scaffold. Since no parameters other than pressure need to be specified, GOSTSHYP allows straightforward geometry optimizations and ab initio molecular dynamics simulations of chemical systems under pressure for nonexpert users. In this work, calculated energies, bond lengths, and dipole moments under pressure fall within the range of established computational methods for high-pressure chemistry. A Diels-Alder reaction and the cyclotrimerization of acetylene showcase the ability of GOSTSHYP to model pressure-induced chemical reactions. The connection to mechanochemistry is pointed out.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Tensor Network Path Integral Study of Dynamics in B850 LH2 Ring with Atomistically Derived Vibrations

The recently introduced multisite tensor network path integral (MS-TNPI) allows simulation of extended quantum systems coupled to dissipative media. We use MS-TNPI to simulate the exciton transport and the absorption spectrum of a B850 bacteriochlorophyll (BChl) ring. The MS-TNPI network is extended to account for the ring topology of the B850 system. Accurate molecular-dynamics-based description of the molecular vibrations and the protein scaffold is incorporated through the framework of Feynman–Vernon influence functional. To relate the present work with the excitonic picture, an exploration of the absorption spectrum is done by simulating it using approximate and topologically consistent transition dipole moment vectors. Comparison of these numerically exact MS-TNPI absorption spectra are shown with second-order cumulant approximations. Finally, the effect of temperature on both the exact and the approximate spectra is also explored.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

Identification of Potent and Selective Inhibitors of Acanthamoeba : Structural Insights into Sterol 14α-Demethylase as a Key Drug Target

Acanthamoeba are free-living pathogenic protozoa that cause blinding keratitis, disseminated infection, and granulomatous amebic encephalitis, which is generally fatal. The development of efficient and safe drugs is a critical unmet need. Acanthamoeba sterol 14α-demethylase (CYP51) is an essential enzyme of the sterol biosynthetic pathway. Repurposing antifungal azoles for amoebic infections has been reported, but their inhibitory effects on Acanthamoeba CYP51 enzymatic activity have not been studied. Here, we report catalytic properties, inhibition, and structural characterization of CYP51 from Acanthamoeba castellanii. The enzyme displays a 100-fold substrate preference for obtusifoliol over lanosterol, supporting the plant-like cycloartenol-based pathway in the pathogen. The strongest inhibition was observed with voriconazole (1 h IC 50 0.45 μM), VT1598 (0.25 μM), and VT1161 (0.20 μM). The crystal structures of A. castellanii CYP51 with bound VT1161 (2.24 Å) and without an inhibitor (1.95 Å), presented here, can be used in the development of azole-based scaffolds to achieve optimal amoebicidal effectiveness.

60 APPLIED LIFE SCIENCES↗

Structure-Based Discovery and Development of Highly Potent Dihydroorotate Dehydrogenase Inhibitors for Malaria Chemoprevention

Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drug resistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malaria through human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-based computational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazolebased Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compounds were identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malaria infection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism and excretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthly chemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used for monthly chemoprevention in Africa to support malaria elimination efforts.

60 APPLIED LIFE SCIENCES↗