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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 415 records · Page 23
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

SARS-CoV-2 spike protein variant binding affinity to an angiotensin-converting enzyme 2 fusion glycoproteins

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the Coronavirus disease 2019 (Covid-19) pandemic, continues to evolve and circulate globally. Current prophylactic and therapeutic countermeasures against Covid-19 infection include vaccines, small molecule drugs, and neutralizing monoclonal antibodies. SARS-CoV-2 infection is mainly mediated by the viral spike glycoprotein binding to angiotensin converting enzyme 2 (ACE2) on host cells for viral entry. As emerging mutations in the spike protein evade efficacy of spike-targeted countermeasures, a potential strategy to counter SARS-CoV-2 infection is to competitively block the spike protein from binding to the host ACE2 using a soluble recombinant fusion protein that contains a human ACE2 and an IgG1-Fc domain (ACE2-Fc). Here, we have established Chinese Hamster Ovary (CHO) cell lines that stably express ACE2-Fc proteins in which the ACE2 domain either has or has no catalytic activity. The fusion proteins were produced and purified to partially characterize physicochemical properties and spike protein binding. Our results demonstrate the ACE2-Fc fusion proteins are heavily N-glycosylated, sensitive to thermal stress, and actively bind to five spike protein variants (parental, alpha, beta, delta, and omicron) with different affinity. Our data demonstrates a proof-of-concept production strategy for ACE2-Fc fusion glycoproteins that can bind to different spike protein variants to support the manufacture of potential alternative countermeasures for emerging SARS-CoV-2 variants.

60 APPLIED LIFE SCIENCES↗
NASA NTRS1998

The Composition of Centaur 5145 Pholus

We present a new spectrum of the Centaur object 5145 Pholus between 1.15 and 2.4 micro meters. We model this, and the previously published (0.4- to 1.0- micrometer) spectrum, using Hapke scattering theory. Seen in absorption are the 2.04- micrometer band of H2O ice and a strong band at 2.27 micrometer, interpreted as frozen methanol and/or a photolytic product of methanol having small molecular weight. The presence of small molecules is indicative of a chemically primitive surface, since heating and other processes remove the light hydrocarbons in favor of macromolecular carbon of the kind found in carbonaceous meteorites. The unusually red slope of Pholus' spectrum is matched by fine grains of a refractory organic solid (tholin). Olivine (which we model with Fo 82) also appears to be present on Pholus. We present a five-component model for the composite spectrum of all spectroscopic and photometric data available for 5145 Pholus and conclude that this is a primitive object which has not yet been substantially processed by solar heat. The properties of Pholus are those of the nucleus of a large comet that has never been active.

Cruikshank, D. P.↗
DOE OSTI2021

Discovery of TAK-981, a First-in-Class Inhibitor of SUMO-Activating Enzyme for the Treatment of Cancer

SUMOylation is a reversible post-translational modification that regulates protein function through covalent attachment of small ubiquitin-like modifier (SUMO) proteins. The process of SUMOylating proteins involves an enzymatic cascade, the first step of which entails the activation of a SUMO protein through an ATP-dependent process catalyzed by SUMO-activating enzyme (SAE). Here, we describe the identification of TAK-981, a mechanism-based inhibitor of SAE which forms a SUMO–TAK-981 adduct as the inhibitory species within the enzyme catalytic site. Optimization of selectivity against related enzymes as well as enhancement of mean residence time of the adduct were critical to the identification of compounds with potent cellular pathway inhibition and ultimately a prolonged pharmacodynamic effect and efficacy in preclinical tumor models, culminating in the identification of the clinical molecule TAK-981.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2022

The P132H mutation in the main protease of Omicron SARS-CoV-2 decreases thermal stability without compromising catalysis or small-molecule drug inhibition

The ongoing SARS-CoV-2 pandemic continues to be a significant threat to global health. First reported in November 2021, the Omicron variant (B.1.1.529) is more transmissible and can evade immunity better than previous SARS-CoV-2 variants, fueling an unprecedented surge in cases. To produce functional proteins from its polyprotein, SARS-CoV-2 relies on the cysteine proteases Nsp3/papain-like protease (PL pro ) and Nsp5/main protease (M pro )/3C-like protease to cleave at three and more than 11 sites, respectively. Therefore, M pro and PL pro inhibitors are considered to be one of the most promising SARS-CoV-2 antivirals. On December 22, 2021, the Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for PAXLOVID, a ritonavir-boosted formulation of nirmatrelvir. Nirmatrelvir is a first-in-class orally bioavailable SARS-CoV-2 M pro inhibitor. Thus, the scientific community must vigilantly monitor potential mechanisms of drug resistance, especially because SARS-CoV-2 is naïve to M pro inhibitors. Mutations have been well identified in variants to this point. Notably, Omicron M pro (OM pro ) harbors a single mutation—P132H. Here, we characterized the enzymatic activity, drug inhibition, and structure of OM pro while evaluating the past and future implications of M pro mutations.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2026

Final Report for Electro-oxidative valorization of biomass: design strategies for selective and stable catalysis

This project aimed to develop a fundamental understanding of the factors that dictate activity and selectivity during electrochemical partial oxidation of multi-carbon organic molecules derived from biomass. Value-adding selective conversions of alcohols to aldehydes, and aldehydes to carboxylic acids were considered, with the ultimate goal to establish general principles for controlling selectivity in organic oxidations. Specific aims involved the use of furfural (FF) and 5-hydoxymethyfurfural (HMF) as model systems and seek to develop knowledge for control of mechanisms that permit selective conversions between oxygenate functional groups with prevention or control of C-C cleavage steps. Another major focus of the work was in achieving these transformations in acidic conditions, which contrasts most existing work (done in base), but is crucial toward compatibility with common pretreatments used to generate small molecules from lignocellulose (e.g. acid hydrolysis or pyrolysis). The work involved well-defined catalyst material synthesis, comparative kinetics, and operando spectroscopies (PI Holewinski), supported by quantum chemical simulations (PI Janik), enabling progress toward efficient, acid-stable oxidation catalysis for biomass upgrading.

Holewinski, Adam [University of Colorado Boulder] ↗
DOE OSTI2021

Effects of support and promoter on Ru catalyst activity in microwave-assisted ammonia synthesis

Microwave-assisted ammonia synthesis is a promising alternative to the energy-intensive Haber-Bosch process, specially at small- and medium-scale with renewable H 2 as resource. Here, we report that Cs promoted Ru/CeO 2 catalyst exhibits considerable activity at 533 K and ambient pressure. In this work, the combined theoretical and experimental approaches are adopted to optimize the electronic and geometric structures of Ru on the catalysts. Both DFT modeling work and structural characterization show that the strong interaction between Ru and CeO 2 results in the formation of highly dispersed Ru particles favoring ammonia synthesis. The higher electron donating ability of CeO 2 and lower electronegativity of Cs promoter result in higher electron density on Ru reducing the N≡N dissociation barrier. Finally, the work demonstrates the potential of microwave-assisted catalytic process in activating stable molecules for ammonia synthesis.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2024

Neutrons in Structural Biology: Challenges and Opportunities (Workshop Report)

Gaining a thorough understanding of biological systems requires building our knowledge about biological processes from the level of atoms and electrons, and up to whole organisms. Such comprehensive knowledge will allow for a predictive understanding of complex biological systems behavior. It will guide us in the design and development of novel therapeutics and vaccines to tackle existing health threats and to prepare for future pandemics, and it will provide information necessary to create new biomaterials and bio-inspired technologies through manipulation of biological macromolecules, their assemblies, single cells and even microorganisms. Reaching these goals will require a synergistic combination of multiple experimental techniques with molecular calculations and predictive simulations, and the design and development of new techniques and capabilities that bridge current knowledge and technology gaps. Neutron scattering provides unique information about the biomacromolecular structure and function and can play a major role in achieving these goals. A workshop was held to engage the scientific community in identifying pressing challenges in biochemistry, structural biology, enzymology and structure-guided drug design not solved with the current neutron scattering technologies or utilizing other structural biology techniques such as X-ray crystallography, NMR, and cryo-EM. The workshop brought together structural biology, biochemistry and computational experts, as well as early career researchers and students, creating a forum for discussing scientific advancement and collaboration. The workshop included a one-day satellite training workshop where graduate students and postdoctoral researchers were educated in the application of neutron crystallography and small-angle scattering in structural biology. Furthermore, the Instrument Scientific Advisory Board (ISAB) for the development of a macromolecular neutron diffractometer at ORNL’s Second Target Station was introduced at the workshop. The major outcome was that neutrons can provide atomic-level understanding of biomacromolecular structure, function and dynamics which is of paramount importance for addressing the identified challenges. Neutron crystallography, in particular, can resolve long-standing biochemical issues regarding enzyme function by delineating the underlying chemistry and can have a major impact on the design of small-molecule therapeutics, especially in combination with molecular computation (quantum chemistry and molecular dynamics simulations) and the emerging artificial intelligence (AI)-assisted drug design technologies. The unique properties of neutrons, including their high sensitivity to hydrogen and their non-destructive nature, make them ideal probes of biological matter. There is a palpable need in the scientific community to expand and enhance the impact of neutron sciences on biology. Neutron crystallography is the only structural biology method capable of determining positions of all hydrogen atoms in proteins, nucleic acids and their complexes at near-physiological temperatures and of unstable species at cryogenic temperatures. Moreover, neutron analysis is non-ionizing, non-destructive and does not perturb the structure or redox chemistry of active site metal centers and clusters in proteins, which can be invaluable for studying radiation-sensitive metalloprotein complexes. Further, neutron energies used in scattering applications are similar to atomic motions, permitting neutron spectroscopies to characterize the dynamics of biomacromolecules on the picosecond to microsecond timescales. The different sensitivities of neutrons to protium (H) and deuterium (D) isotopes of hydrogen allow enhanced visibility of specific parts of biological complexes through isotopic labeling. The impact of neutrons will be most powerful when neutron scattering is combined with complementary experimental techniques that use photons and electrons, and with high-performance computing. The interconnection and mutuality of the experimental and theoretical capabilities will drive discoveries in biological and health sciences to generate more complete picture of complex biological systems. The major limitation in the field of biological neutron crystallography has been signal-to-noise, demanding large samples that are difficult to produce for the majority of biomacromolecules and limiting the applicability of this technique in biological sciences. A neutron crystallography instrument at the Second Target Station will revolutionize biological science with neutrons by engaging a large scientific community of structural biologists, enabling successful neutron diffraction experiments from radically smaller biomacromolecular crystals, resolving unanswered biochemical questions, and meaningfully contributing to rational drug design. The meeting highlighted 10 grand challenges that will be addressed with this advanced capability over the next decade and beyond, and the recommendations required to help address them are given below.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Topography and canopy cover influence soil organic carbon composition and distribution across a forested hillslope in the discontinuous permafrost zone

Abstract Topography and canopy cover influence ground temperature in warming permafrost landscapes, yet soil temperature heterogeneity introduced by mesotopographic slope positions, microtopographic differences in vegetation cover, and the subsequent impact of contrasting temperature conditions on soil organic carbon (SOC) dynamics are understudied. Buffering of permafrost‐affected soils against warming air temperatures in boreal forests can reflect surface soil characteristics (e.g., thickness of organic material) as well as the degree and type of canopy cover (e.g., open cover vs. closed cover). Both landscape and soil properties interact to determine meso‐ and microscale heterogeneity of ground warming. We sampled a hillslope catena transect in a discontinuous permafrost zone near Fairbanks, Alaska, to test the small‐scale (1 to 3 m) impacts of slope position and cover type on soil organic matter composition. Mineral active layer samples were collected from backslope, low backslope, and footslope positions at depths spanning 19 to 60 cm. We examined soil mineralogical composition, soil moisture, total carbon and nitrogen content, and organic mat thickness in conjunction with an assessment of SOC composition using Fourier‐transform ion cyclotron resonance mass spectrometry (FT‐ICR‐MS). Soils in the footslope position had a higher relative contribution of lignin‐like compounds, whereas backslope soils had more aliphatic and condensed aromatic compounds as determined using FT‐ICR‐MS. The effect of open versus closed tree canopy cover varied with the slope position. On the backslope, we found higher oxidation of molecules under open cover than closed cover, indicating an effect of warmer soil temperature on decomposition. Little to no effect of the canopy was observed in soils at the footslope position, which we attributed, in part, to the strong impact of soil moisture content in SOC dynamics in the water‐gathering footslope position. The thin organic mat under open cover on the backslope position may have contributed to differences in soil temperature and thus SOC oxidation under open and closed canopies. Here, the thinner organic mat did not appear to buffer the underlying soil against warm season air temperatures and thus increased SOC decomposition as indicated by the higher oxidation of SOC molecules and a lower contribution of simple molecules under open cover than the closed canopy sites. Our findings suggest that the role of canopy cover in SOC dynamics varies as a function of landscape position and soil properties, namely, organic mat thickness and soil moisture. Condition‐specific heterogeneity of SOC composition under open and closed canopy cover highlights the protective effect of canopy cover for soils on backslope positions.

54 ENVIRONMENTAL SCIENCES↗
DOE OSTI2020

Isotopic Studies for Tracking Biogenic Carbon during Co-processing of Biomass and Vacuum Gas Oil

Co-processing bio-oils with petroleum-derived feeds in the existing multitrillion dollar refining and distribution infrastructure is an attractive option for introducing renewable energy into the fuels marketplace. Considerable research on co-processing bio-oils and vacuum gas oil (VGO) in fluid catalytic cracking units (FCC) using equilibrium catalysts (E-Cats) demonstrated that biomass-derived molecules decreased activity of and increased carbon laydown on E-Cat. In this work, 13 C-labeled biomass was co-processed with VGO using either an E-Cat or a proprietary zeolite Johnson Matthey catalyst (CP758), which is optimzed for upgrading biomass vapors in a riser reactor, to evaluate the fate of biogenic carbon in FCC products. The results from both catalysts indicate that biogenic carbon was incorporated into alkenes and aromatic hydrocarbons. While no biogenic carbon was found in linear alkanes, it was observed in cycloalkanes during experiments with E-Cat but not with CP758. All produced CO2 was biogenic as was most of the carbon laydown on the catalysts. Several partially deoxygenated biomass compounds, such as alkylphenols and benzofurans, unexpectedly contained small amounts of carbon from VGO. Although this study was conducted with labeled biomass and not bio-oil, it provides insights to reaction mechanisms for co-processing bio-oil and VGO in an FCC, which is required to develop catalysts that efficiently convert bio-oil components during FCC co-processing. This work also demonstrates that comprehensive catalyst development utilizing both biomass- and fossil-derived feeds is required to maximize the incorporation of biogenic carbon into transportation fuels.

09 BIOMASS FUELS↗
DOE OSTI2025

Conformational flexibility is a critical factor in designing broad-spectrum human norovirus protease inhibitors

Human norovirus (HuNoV) is a leading cause of gastroenteritis worldwide and is associated with significant morbidity, mortality, and economic impact. There are currently no licensed antiviral drugs for the treatment of HuNoV-associated gastroenteritis. The HuNoV protease plays a critical role in the initiation of virus replication by cleaving the polyprotein. Thus, it is an ideal target for developing antiviral small-molecule inhibitors. While rupintrivir, a potent small-molecule inhibitor of several picornavirus proteases, effectively inhibits GI.1 protease, it is an order of magnitude less effective against GII protease. Other GI.1 protease inhibitors also tend to be less effective against GII proteases. To understand the structural basis for the potency difference, we determined the crystal structures of proteases of GI.1, pandemic GII.4 (Houston and Sydney), and GII.3 in complex with rupintrivir. These structures show that the open substrate pocket in GI protease binds rupintrivir without requiring significant conformational changes, whereas, in GII proteases, the closed pocket flexibly extends, reorienting arginine-112 in the BII-CII loop to accommodate rupintrivir. Structures of R112A protease mutants with rupintrivir, coupled with enzymatic and inhibition studies, suggest R112 is involved in displacing both substrate and ligands from the active site, implying a role in the release of cleaved products during polyprotein processing. Thus, the primary determinant for differential inhibitor potency between the GI and GII proteases is the increased flexibility in the BII-CII loop of the GII proteases caused by the H-G mutation in this loop. Therefore, the inherent flexibility of the BII-CII loop in GII proteases is a critical factor to consider when developing broad-spectrum inhibitors for HuNoV proteases.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

Topography and canopy cover influence soil organic carbon composition and distribution across a forested hillslope in the discontinuous permafrost zone

This dataset contains data used for the paper "Topography and canopy cover influence soil organic carbon composition and distribution across a forested hillslope in the discontinuous permafrost zone". The Related References field will be updated with a full citation when available. Topography and canopy cover influence ground temperature in warming permafrost landscapes, yet soil temperature heterogeneity introduced by meso-topographic slope positions, microtopographic differences in vegetation cover, and the subsequent impact of contrasting temperature conditions to soil organic carbon (SOC) dynamics are understudied. Buffering of permafrost-affected soils against warming air temperatures in boreal forests can reflect surface soil characteristics (e.g., thickness of organic material) as well as the degree and type of canopy cover (e.g., open cover vs closed cover). Both landscape and soil properties interact to determine meso- and micro-scale heterogeneity of ground warming. We sampled a hillslope catena transect in a discontinuous permafrost zone near Fairbanks, Alaska to test the small-scale (1 to 3 meter) impacts of slope position and cover type on soil organic matter composition. Mineral active layer samples were collected from backslope, low backslope, and footslope positions at depths spanning 19 to 60 cm. We examined soil mineralogical composition, soil moisture, total carbon and nitrogen content, and organic mat thickness in conjunction with an assessment of SOC composition using Fourier-transform ion Cyclotron Resonance Mass Spectrometry (FT-ICR-MS). Soils in the footslope position had a higher relative contribution of lignin-like compounds while backslope soils had more aliphatic and condensed aromatic compounds as determined by FT-ICR-MS. The effect of open versus closed tree canopy cover varied with slope position. On the backslope, we found higher oxidation of molecules under open cover compared with closed cover, indicating an effect of warmer soil temperature on decomposition. Little to no effect of canopy was observed for soils at the footslope position, which we attributed, in part, to the strong impact of soil moisture content in SOC dynamics in the water-gathering footslope position. The thin organic mat under open cover on the backslope position may have contributed to differences in soil temperature and thus SOC oxidation under open and closed canopy. Here, the thinner organic mat did not appear to buffer the underlying soil against warm season air temperatures and thus increased SOC decomposition as indicated by higher oxidation of SOC molecules and a lower contribution of simple molecules under open cover compared with the closed canopy sites. Our findings suggest that the role of canopy cover in SOC dynamics varies as a function of landscape position and soil properties, namely organic mat thickness and soil moisture. Condition-specific heterogeneity of SOC composition under open and closed canopy cover highlights the protective effect of canopy cover for soils on backslope positions. This dataset contains a compressed (.zip) archive of the data and R scripts used for this manuscript. The dataset includes files in .csv format, which can be accessed and processed using MS Excel or R. This archive can also be accessed on GitHub at https://github.com/Erin-Rooney/Y1_fairbanks (DOI: 10.5281/zenodo.8071247).

54 ENVIRONMENTAL SCIENCES↗
NASA NTRS2001

Biotechnology Approaches to Life Detection

The direct detection of organic biomarkers for living or fossil microbes on Mars by an in situ instrument is a worthy goal for future lander missions. Several new and innovative biotechnology approaches are being explored. Firstly we have proposed an instrument based on immunological reactions to specific antibodies to cause activation of fluorescent stains. Antibodies are raised or acquired to a variety of general and specific substances that might be in Mars soil. These antibodies are then combined with various fluorescent stains and applied to micron sized numbered spots on a small (2-3 cm) test plate where they become firmly attached after freeze drying. Using technology that has been developed for gene mining in DNA technology up to 10,000 tests per square inch can now be applied to a test plate. On Mars or the planet/moon of interest, a sample of soil from a trench or drill core is extracted with water and/or an organic solvent and ultrasonication and then applied to the test plate. Any substance, which has an antibody on the test plate, will react with its antibody and activate its fluorescent stain. At the moment a small UV light source will illuminate the test plate, which is observed with a small CCD camera, although other detection systems will be applied. The numbered spots that fluoresce indicate the presence of the tested-for substance, and the intensity indicates relative amounts. Furthermore with up to a thousand test plates available false positives and several variations of antibody can also be screened for. The entire instrument can be quite small and light, on the order of 10 cm in each dimension. A possible choice for light source may be small UV lasers at several wavelengths. Some of the wells or spots can contain simply standard fluorescent stains used to detect live cells, dead cells, DNA, etc. The stains in these spots may be directly activated, with no antibodies being necessary. The proposed system will look for three classes of biomarkers: those from extant life, such as DNA, those from extinct life such as hopanes, and those from organic compounds not necessarily associated with life such as PAHs, rocket exhaust contamination and other a/pre-biotic chemicals. Both monoclonal and polyclonal antibodies can be used. Monoclonal antibodies react with a very specific compound, but polyclonal antibodies may react to any of a whole family of compounds. Furthermore the technique of phage display to raise antibodies against classically non-antigenic molecules is also being considered. Additional information is contained in the original extended abstract.

Steele, Andrew↗
DOE OSTI2021

Discovery of Small-Molecule Inhibitors of SARS-CoV-2 Proteins Using a Computational and Experimental Pipeline

A rapid response is necessary to contain emergent biological outbreaks before they can become pandemics. The novel coronavirus (SARS-CoV-2) that causes COVID-19 was first reported in December of 2019 in Wuhan, China and reached most corners of the globe in less than two months. In just over a year since the initial infections, COVID-19 infected almost 100 million people worldwide. Although similar to SARS-CoV and MERS-CoV, SARS-CoV-2 has resisted treatments that are effective against other coronaviruses. Crystal structures of two SARS-CoV-2 proteins, spike protein and main protease, have been reported and can serve as targets for studies in neutralizing this threat. We have employed molecular docking, molecular dynamics simulations, and machine learning to identify from a library of 26 million molecules possible candidate compounds that may attenuate or neutralize the effects of this virus. The viability of selected candidate compounds against SARS-CoV-2 was determined experimentally by biolayer interferometry and FRET-based activity protein assays along with virus-based assays. In the pseudovirus assay, imatinib and lapatinib had IC 50 values below 10 μM, while candesartan cilexetil had an IC 50 value of approximately 67 µM against M pro in a FRET-based activity assay. Comparatively, candesartan cilexetil had the highest selectivity index of all compounds tested as its half-maximal cytotoxicity concentration 50 (CC 50 ) value was the only one greater than the limit of the assay (>100 μM).

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A static quantum embedding scheme based on coupled cluster theory

Here, we develop a static quantum embedding scheme that utilizes different levels of approximations to coupled cluster (CC) theory for an active fragment region and its environment. To reduce the computational cost, we solve the local fragment problem using a high-level CC method and address the environment problem with a lower-level Møller–Plesset (MP) perturbative method. This embedding approach inherits many conceptual developments from the hybrid second-order Møller–Plesset (MP2) and CC works by Nooijen [J. Chem. Phys. 111, 10815 (1999)] and Bochevarov and Sherrill [J. Chem. Phys. 122, 234110 (2005)]. We go beyond those works here by primarily targeting a specific localized fragment of a molecule and also introducing an alternative mechanism to relax the environment within this framework. We will call this approach MP-CC. We demonstrate the effectiveness of MP-CC on several potential energy curves and a set of thermochemical reaction energies, using CC with singles and doubles as the fragment solver, and MP2-like treatments of the environment. The results are substantially improved by the inclusion of orbital relaxation in the environment. Using localized bonds as the active fragment, we also report results for N=N bond breaking in azomethane and for the central C–C bond torsion in butadiene. We find that when the fragment Hilbert space size remains fixed (e.g., when determined by an intrinsic atomic orbital approach), the method achieves comparable accuracy with both a small and a large basis set. Additionally, our results indicate that increasing the fragment Hilbert space size systematically enhances the accuracy of observables, approaching the precision of the full CC solver.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2023

Anti-fungal bioactive terpenoids in the bioenergy crop switchgrass (Panicum virgatum) may contribute to ecotype-specific microbiome composition

Abstract Plant derived bioactive small molecules have attracted attention of scientists across fundamental and applied scientific disciplines. We seek to understand the influence of these phytochemicals on rhizosphere and root-associated fungi. We hypothesize that – consistent with accumulating evidence that switchgrass genotype impacts microbiome assembly – differential terpenoid accumulation contributes to switchgrass ecotype-specific microbiome composition. An initial in vitro Petri plate-based disc diffusion screen of 18 switchgrass root derived fungal isolates revealed differential responses to upland- and lowland-isolated metabolites. To identify specific fungal growth-modulating metabolites, we tested fractions from root extracts on three ecologically important fungal isolates – Linnemania elongata, Trichoderma sp. and Fusarium sp. Saponins and diterpenoids were identified as the most prominent antifungal metabolites. Finally, analysis of liquid chromatography-purified terpenoids revealed fungal inhibition structure – activity relationships (SAR). Saponin antifungal activity was primarily determined by the number of sugar moieties – saponins glycosylated at a single core position were inhibitory whereas saponins glycosylated at two core positions were inactive. Saponin core hydroxylation and acetylation were also associated with reduced activity. Diterpenoid activity required the presence of an intact furan ring for strong fungal growth inhibition. These results inform future breeding and biotechnology strategies for crop protection with reduced pesticide application.

09 BIOMASS FUELS↗
DOE OSTI2022

Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho

Fibroblast growth factor 23 (FGF23) is a therapeutic target for treating hereditary and acquired hypophosphatemic disorders, such as X-linked hypophosphatemic (XLH) rickets and tumor-induced osteomalacia (TIO), respectively. FGF23-induced hypophosphatemia is mediated by signaling through a ternary complex formed by FGF23, the FGF receptor (FGFR), and α-Klotho. Currently, disorders of excess FGF23 are treated with an FGF23-blocking antibody, burosumab. Small-molecule drugs that disrupt protein/protein interactions necessary for the ternary complex formation offer an alternative to disrupting FGF23 signaling. In this study, the FGF23:α-Klotho interface was targeted to identify small-molecule protein/protein interaction inhibitors since it was computationally predicted to have a large fraction of hot spots and two druggable residues on α-Klotho. We further identified Tyr433 on the KL1 domain of α-Klotho as a promising hot spot and α-Klotho as an appropriate drug-binding target at this interface. Subsequently, we performed in silico docking of ~5.5 million compounds from the ZINC database to the interface region of α-Klotho from the ternary crystal structure. Following docking, 24 and 20 compounds were in the final list based on the lowest binding free energies to α-Klotho and the largest number of contacts with Tyr433, respectively. Herein, five compounds were assessed experimentally by their FGF23-mediated extracellular signal-regulated kinase (ERK) activities in vitro, and two of these reduced activities significantly. Both these compounds were predicted to have favorable binding affinities to α-Klotho but not have a large number of contacts with the hot spot Tyr433. ZINC12409120 was found experimentally to disrupt FGF23:α-Klotho interaction to reduce FGF23-mediated ERK activities by 70% and have a half maximal inhibitory concentration (IC50) of 5.0 ± 0.23 μM. Molecular dynamics (MD) simulations of the ZINC12409120:α-Klotho complex starting from in silico docking poses reveal that the ligand exhibits contacts with residues on the KL1 domain, the KL1–KL2 linker, and the KL2 domain of α-Klotho simultaneously, thereby possibly disrupting the regular function of α-Klotho and impeding FGF23:α-Klotho interaction. ZINC12409120 is a candidate for lead optimization.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS1997

Computer-aided design of a proton pump

The use of transmembrane proton gradients in energy transduction is an almost universal feature of life on earth. These proton gradients are established and maintained by specialized assemblies of proteins which actively pump protons across membranes. One broad class of proton pumps uses captured light energy to drive the proton pumping. Our goal is to elucidate the minimum structural requirements of a light-driven proton-pump. There are two basic components to a simple light-driven proton pump: a source of photo-generated protons and a "gate-keeper" which prevents these protons from reattaching themselves to their source. A wide variety of molecules in the membrane, even as simple as polycyclic aromatic hydrocarbons, are capable of releasing protons when illuminated. Our work is therefore focused on the design of the "gate-keeper." Our initial model involves a pair of proton acceptors, coupled to each other by a transient water bridge, and supported in the membrane by a small bundle of peptide helices. Upon illumination, the proton source transfers its proton to the:- first acceptor of the gate-keeper. While the reverse reaction is highly probable, all that is needed to ensure irreversibility is a nonvanishing probability that the proton will be transferred to the second acceptor across a transient water bridge. Back transfer of the proton to the first acceptor, and thence to the proton source, is impeded by the free energy required to move the proton uphill towards the. proton source and by the disruption of the transient water bridge. As a prototypical water-bridged proton transfer system, we are studying the transfer of a proton across a water bridge from a formic acid to a formate anion. With a pK(sub alpha), of 3.7. formic acid is a good model for the acidic amino acids glutamate and aspartate which are good candidates for gate-keeper proton acceptors. Simulations of proton transfer reactions in a membrane are complicated by the quantum mechanical nature of the process breaking and forming chemical bonds.

New, Michael H.↗
DOE OSTI2024

Self-compensation of group-V acceptors in CdTe

Cadmium Telluride is at the core of an important thin-film technology for photovoltaics that is already commercially available, yet the CdTe-based solar cell efficiency remains limited at 22%, well below the theoretical limit of ~30%. Increasing the hole concentration is crucial for higher efficiency, and group-V elements such as As, P, and Sb are potential dopants as they are shallow acceptors. Nevertheless, group-V doped p-type CdTe often exhibits low doping activation, and the compensation source remains debated. Here, we performed hybrid density functional calculations with spin-orbit coupling to investigate possible sources of hole compensation in group-V doped CdTe. First, regarding possible self-compensation of the group-V dopants, we find that the formation of AX centers is unlikely since they are found to be unstable relative to the shallow acceptor forms. However, if the group-V dopants come in during growth (such as dimer molecules As2, P2, and Sb2), we find that the impurity atoms, which would occupy nearest neighbor sites, maintain the V-V bonds, limiting the hole density. For the native defects, our study reveals that Cd interstitial is the lowest energy donor defect in p-type CdTe. Still, it has a small migration barrier of 0.5 eV, making it highly mobile and unstable at room temperature. The Te vacancy is the next lowest formation energy donor. The migration barrier of 1.4 eV indicates that the Te vacancy is stable at room temperature. The antisite CdTe is also a donor, with low formation energy and stable at room temperature, potentially limiting the hole concentration. Our results, therefore, shed light on possible compensation centers and some guidance on how to avoid them.

14 SOLAR ENERGY↗