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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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46 records · Page 3
All sourcesNASA NTRSDOE OSTI
DOE OSTI2020

Computational Study of an Iron(II) Polypyridine Electrocatalyst for CO 2 Reduction: Key Roles for Intramolecular Interactions in CO 2 Binding and Proton Transfer

A solar-driven conversion of CO 2 into fuels by artificial photosynthesis would not only mitigate the greenhouse effect but also provide an alternative to obtain fuels in a renewable fashion. To this end, the new iron polypyridine catalyst [Fe(bpy NHEt PY2Me)L 2 ] 2+ (L = H 2 O, CH 3 CN) was recently developed for the electrochemical reduction of CO 2 to CO. Here, we performed density functional theory (DFT) electronic structure calculations to shed light on a possible pathway for CO 2 reduction and the origin of the selectivity between CO 2 reduction versus the hydrogen evolution reaction. The metal center remains Lewis acidic throughout the reduction process due to ligand loss and mainly ligand-based reduction stabilized by antiferromagnetic coupling to a high-spin Fe(II) center. This results in a high barrier for hydride formation but a facile addition and activation of CO 2 via an η 2 coordination and stabilizing hydrogen bonding by the amine group. The second unoccupied equatorial coordination site opens up the possibility for an intramolecular protonation with a coordinated water ligand. This facilitates protonation because not only CO 2 but also the proton source H 2 O is activated and properly aligned for a proton transfer due to the Fe-OH 2 bond; consequently, both protonation steps are facile. The moderate ligand field allows a rapid ligand exchange for a second intramolecular protonation step and facilitates an exergonic CO release. The lower selectivity of the related [Fe(bpy OH PY2Me)L 2 ] 2+ complex can be related to its more acidic second coordination sphere, which enables an intramolecular proton transfer that is kinetically competitive with CO 2 addition.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2025

Differentiating Ligand Tailoring and Cation Incorporation as Strategies for Tuning Heterobimetallic Cerium Complexes

Tuning of redox-active complexes featuring metals with high coordination numbers by incorporation of secondary redox-inactive cations has received far less attention than it deserves. Here, appending moderate steric bulk to a tripodal ligand framework has been tested for its influence on secondary-cation-driven structural and electrochemical tuning of cerium, a lanthanide that tends to adopt high coordination numbers. A quasi -C 3 -symmetric cerium(III) complex denoted [Ce] has been prepared that features pendant benzyloxy groups, and this work demonstrates that this species offers a site capable of binding single Na + or Ca 2+ ions. Electrochemical and UV-visible spectroscopic studies reveal equilibrium binding affinity of [Ce] for Na + in acetonitrile solvent, contrasting with tight binding of all cations in all other previously studied systems of this type. The modulated cation binding can be attributed to the bulky benzyloxy groups, which impact the thermodynamics of cation binding but do not impede the formation of cerium centers with coordination number 8 upon binding of either Na + or Ca2 + . Finally, the Ce(IV/III) reduction potential was found to be tunable under the equilibrium binding conditions, highlighting the potentially significant role that controlled structural changes can play in modulating the solution properties of heterobimetallic complexes.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS2003

Crystal structures of pinoresinol-lariciresinol and phenylcoumaran benzylic ether reductases and their relationship to isoflavone reductases

Despite the importance of plant lignans and isoflavonoids in human health protection (e.g. for both treatment and prevention of onset of various cancers) as well as in plant biology (e.g. in defense functions and in heartwood development), systematic studies on the enzymes involved in their biosynthesis have only recently begun. In this investigation, three NADPH-dependent aromatic alcohol reductases were comprehensively studied, namely pinoresinol-lariciresinol reductase (PLR), phenylcoumaran benzylic ether reductase (PCBER), and isoflavone reductase (IFR), which are involved in central steps to the various important bioactive lignans and isoflavonoids. Of particular interest was in determining how differing regio- and enantiospecificities are achieved with the different enzymes, despite each apparently going through similar enone intermediates. Initially, the three-dimensional x-ray crystal structures of both PLR_Tp1 and PCBER_Pt1 were solved and refined to 2.5 and 2.2 A resolutions, respectively. Not only do they share high gene sequence similarity, but their structures are similar, having a continuous alpha/beta NADPH-binding domain and a smaller substrate-binding domain. IFR (whose crystal structure is not yet obtained) was also compared (modeled) with PLR and PCBER and was deduced to have the same overall basic structure. The basis for the distinct enantio-specific and regio-specific reactions of PCBER, PLR, and IFR, as well as the reaction mechanism and participating residues involved (as identified by site-directed mutagenesis), are discussed.

NASA Discipline Plant Biology↗
DOE OSTI2022

Steric and Lewis Basicity Influence of the Second Coordination Sphere on Electrocatalytic CO 2 Reduction by Manganese Bipyridyl Complexes

This study aims to provide a greater insight into the balance between steric (bpy vs (Ph) 2 bpy vs mes 2 bpy ligands) and Lewis basic ((Ph) 2 bpy vs (MeOPh) 2 bpy vs (MeSPh) 2 bpy ligands) influence on the efficiencies of the protonation-first vs reduction-first CO 2 reduction mechanisms with [Mn I (R 2 bpy)(CO) 3 (CH 3 CN)] + precatalysts, and on their respective transition-state geometries/energies for rate-determining C–OH bond cleavage toward CO evolution. The presence of only modest steric bulk at the 6,6'-diphenyl-2,2'-bipyridyl ((Ph) 2 bpy) ligand has here allowed unique insight into the mechanism of catalyst activation and CO 2 binding by navigating a perfect medium between the nonsterically encumbered bpy-based and the highly sterically encumbered mes2bpy-based precatalysts. Cyclic voltammetry conducted in CO 2 -saturated electrolyte for the (Ph) 2 bpy-based precatalyst [2-CH 3 CN] + confirms that CO 2 binding occurs at the two-electron-reduced activated catalyst [2] – in the absence of an excess proton source, in contrast to prior assumptions that all manganese catalysts require a strong acid for CO 2 binding. This observation is supported by computed free energies of the parent–child reaction for [Mn–Mn] o dimer formation, where increased steric hindrance relative to the bpy-based precatalyst correlates with favorable CO 2 binding. A critical balance must be adhered to, however, as the absence of steric bulk in the bpy-based precatalyst [1-CH 3 CN] + maintains a lower overpotential than [2-CH 3 CN] + at the protonation-first pathway with comparable kinetic performance, whereas an ~2-fold greater TOF max is observed at its reduction-first pathway with an almost identical overpotential as [2-CH 3 CN] + . Notably, excessive steric bulk in the mes2bpy-based precatalyst [3-CH 3 CN] + results in increased activation free energies of the C–OH bond cleavage transition states for both the protonation-first and the reduction-first pathways relative to both [1-CH 3 CN] + and [2-CH 3 CN] + . In fact, [3-CH 3 CN] + requires a 1 V window beyond its onset potential to reach its peak catalytic current, which is in contrast to the narrower (<0.30 V) potential response window of the remaining catalysts here studied. Furthermore, voltammetry recorded under 1 atm of CO 2 with 2.8 M (5%) H 2 O establishes [2-CH 3 CN] + to have the lowest overpotential (η = 0.75 V) in the series here studied, attributed to its ability to lie “on the fence” when providing sufficient steric bulk to hinder (but not prevent) [Mn–Mn] o dimerization, while simultaneously having a limited steric impact on the free energy of activation for the rate-determining C–OH bond cleavage transition state. While the methoxyphenyl bpy-based precatalyst [4-CH 3 CN] + possesses an increased steric presence relative to [2-CH 3 CN] + , this is offset by its capacity to stabilize the C–OH bond cleavage transition states of both the protonation-first and the reduction-first pathways by facilitating second coordination sphere H-bonding stabilization.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
DOE OSTI2022

Developing nanometer scale, atomically precise metallo-catalysts with Molecular Lego

We propose to create atomically precise, highly robust, nanometer scale macromolecules that organize biomimetic metal binding groups in designed three-dimensional pockets to accelerate specific polymerization reactions. These atomically precise catalysts will create atomically precise polymers with improved mechanical and environmental properties from renewable building blocks. We seek to create and study nanometer scale catalysts that mimic metallo-enzymes in their activity and selectivity because these larger catalysts will be able to make more extensive non-covalent contacts with the transition state of the growing polymer. These catalysts will have extended lifetimes because they will better protect the metals and higher activity because additional reactive groups can be brought in close contact with the active site to enhance reactivity. They will be far more tolerant to extremes of temperature and will not denature in non-aqueous solvents because they are held together by multiple, strong, covalent bonds. Our approach to catalysts could be used to develop catalysts to replace noble metal-based catalysts when targeting other reactions, because the geometry of the active site enforced by the Molecular Lego scaffolding will access new reactivity, mimicking how nature uses earth abundant metals for much of its catalysis. We will initially target Lewis acid-based catalysts that assemble aliphatic polyesters with improved stereoselectivity, tacticity and complex alternation of monomers. Aliphatic polyesters have received growing attention as attractive, environmentally benign, and sustainable alternatives to polymers developed from petroleum feedstocks. Aliphatic polyesters are environmentally friendly because they undergo facile hydrolytic degradation to benign products, and they have excellent properties and high biocompatibility. We will assemble these catalysts using unique “Spiroligomers” (aka Molecular Lego) chemistry developed in the Schafmeister group combined with the organometallic chemistry expertise of the Dobereiner group. Polymers are an attractive synthetic target of nanoscale atomically precise catalysts because their resulting structure, stereochemistry and tacticity has profound impact on their properties (crystalline vs amorphous) and provides a readout of the catalytic mechanism. Polymer synthesis also serves as an example of “atomically precise manufacturing” where atomically precise nanoscale catalysts construct polymers with atomic precision at increasing length scales.

32 ENERGY CONSERVATION, CONSUMPTION, AND UTILIZATI↗
DOE OSTI2022

Characterization of Interactions between CTX-M-15 and Clavulanic Acid, Desfuroylceftiofur, Ceftiofur, Ampicillin, and Nitrocefin

Cefotaximase-Munich (CTX-M) extended-spectrum beta-lactamases (ESBLs) are commonly associated with Gram-negative, hospital-acquired infections worldwide. Several beta-lactamase inhibitors, such as clavulanate, are used to inhibit the activity of these enzymes. To understand the mechanism of CTX-M-15 activity, we have determined the crystal structures of CTX-M-15 in complex with two specific classes of beta-lactam compounds, desfuroylceftiofur (DFC) and ampicillin, and an inhibitor, clavulanic acid. The crystal structures revealed that Ser70 and five other residues (Lys73, Tyr105, Glu166, Ser130, and Ser237) participate in catalysis and binding of those compounds. Based on analysis of steady-state kinetics, thermodynamic data, and molecular docking to both wild-type and S70A mutant structures, we determined that CTX-M-15 has a similar affinity for all beta-lactam compounds (ceftiofur, nitrocefin, DFC, and ampicillin), but with lower affinity for clavulanic acid. A catalytic mechanism for tested β-lactams and two-step inhibition mechanism of clavulanic acid were proposed. CTX-M-15 showed a higher activity toward DFC and nitrocefin, but significantly lower activity toward ampicillin and ceftiofur. The interaction between CTX-M-15 and both ampicillin and ceftiofur displayed a higher entropic but lower enthalpic effect, compared with DFC and nitrocefin. DFC, a metabolite of ceftiofur, displayed lower entropy and higher enthalpy than ceftiofur. This finding suggests that compounds containing amine moiety (e.g., ampicillin) and the furfural moiety (e.g., ceftiofur) could hinder the hydrolytic activity of CTX-M-15.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

A bioactive supramolecular and covalent polymer scaffold for cartilage repair in a sheep model

Regeneration of hyaline cartilage in human-sized joints remains a clinical challenge, and it is a critical unmet need that would contribute to longer healthspans. Injectable scaffolds for cartilage repair that integrate both bioactivity and sufficiently robust physical properties to withstand joint stresses offer a promising strategy. We report here on a hybrid biomaterial that combines a bioactive peptide amphiphile supramolecular polymer that specifically binds the chondrogenic cytokine transforming growth factor β-1 (TGFβ-1) and crosslinked hyaluronic acid microgels that drive formation of filament bundles, a hierarchical motif common in natural musculoskeletal tissues. The scaffold is an injectable slurry that generates a porous rubbery material when exposed to calcium ions once placed in cartilage defects. The hybrid material was found to support in vitro chondrogenic differentiation of encapsulated stem cells in response to sustained delivery of TGFβ-1. Using a sheep model, we implanted the scaffold in shallow osteochondral defects and found it can remain localized in mechanically active joints. Evaluation of resected joints showed significantly improved repair of hyaline cartilage in osteochondral defects injected with the scaffold relative to defects injected with the growth factor alone, including implantation in the load-bearing femoral condyle. These results demonstrate the potential of the hybrid biomimetic scaffold as a niche to favor cartilage repair in mechanically active joints using a clinically relevant large-animal model.

Science & Technology - Other Topics↗
DOE OSTI2022

Antigenic Characterization and Pandemic Risk Assessment of North American H1 Influenza A Viruses Circulating in Swine

The first pandemic of the 21st century was caused by an H1N1 influenza A virus (IAV) introduced from pigs into humans, highlighting the importance of swine as reservoirs for pandemic viruses. Two major lineages of swine H1 circulate in North America: the 1A classical swine lineage (including that of the 2009 H1N1 pandemic) and the 1B human seasonal-like lineage. Here, we investigated the evolution of these H1 IAV lineages in North American swine and their potential pandemic risk. We assessed the antigenic distance between the HA of representative swine H1 and human seasonal vaccine strains (1978 to 2015) in hemagglutination inhibition (HI) assays using a panel of monovalent antisera raised in pigs. Antigenic cross-reactivity varied by strain but was associated with genetic distance. Generally, the swine 1A lineage viruses that seeded the 2009 H1 pandemic were antigenically most similar to the H1 pandemic vaccine strains, with the exception of viruses in the genetic clade 1A.1.1.3, which had a two-amino acid deletion mutation near the receptor-binding site, which dramatically reduced antibody recognition. The swine 1B lineage strains, which arose from previously circulating (pre-2009 pandemic) human seasonal viruses, were more antigenically similar to pre-2009 human seasonal H1 vaccine viruses than post-2009 strains. Human population immunity was measured by cross-reactivity in HI assays to representative swine H1 strains. There was a broad range of titers against each swine strain that was not associated with age, sex, or location. However, there was almost no cross-reactivity in human sera to the 1A.1.1.3 and 1B.2.1 genetic clades of swine viruses, and the 1A.1.1.3 and 1B.2.1 clades were also the most antigenically distant to the human vaccine strains. Our data demonstrate that the antigenic distances of representative swine strains from human vaccine strains represent an important part of the rational assessment of swine IAV for zoonotic risk research and pandemic preparedness prioritization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

A sorghum ascorbate peroxidase with four binding sites has activity against ascorbate and phenylpropanoids

Abstract In planta, H2O2 is produced as a by-product of enzymatic reactions and during defense responses. Ascorbate peroxidase (APX) is a key enzyme involved in scavenging cytotoxic H2O2. Here, we report the crystal structure of cytosolic APX from sorghum (Sorghum bicolor) (Sobic.001G410200). While the overall structure of SbAPX was similar to that of other APXs, SbAPX uniquely displayed four bound ascorbates rather than one. In addition to the ɣ-heme pocket identified in other APXs, ascorbates were bound at the δ-meso and two solvent-exposed pockets. Consistent with the presence of multiple binding sites, our results indicated that the H2O2-dependent oxidation of ascorbate displayed positive cooperativity. Bound ascorbate at two surface sites established an intricate proton network with ascorbate at the ɣ-heme edge and δ-meso sites. Based on crystal structures, steady-state kinetics, and site-directed mutagenesis results, both ascorbate molecules at the ɣ-heme edge and the one at the surface are expected to participate in the oxidation reaction. We provide evidence that the H2O2-dependent oxidation of ascorbate by APX produces a C2-hydrated bicyclic hemiketal form of dehydroascorbic acid at the ɣ-heme edge, indicating two successive electron transfers from a single-bound ascorbate. In addition, the δ-meso site was shared with several organic compounds, including p-coumaric acid and other phenylpropanoids, for the potential radicalization reaction. Site-directed mutagenesis of the critical residue at the ɣ-heme edge (R172A) only partially reduced polymerization activity. Thus, APX removes stress-generated H2O2 with ascorbates, and also uses this same H2O2 to potentially fortify cell walls via oxidative polymerization of phenylpropanoids in response to stress.

Plant Sciences↗
DOE OSTI2022

An Activity-Based Oxaziridine Platform for Identifying and Developing Covalent Ligands for Functional Allosteric Methionine Sites: Redox-Dependent Inhibition of Cyclin-Dependent Kinase 4

Activity-based protein profiling (ABPP) is a versatile strategy for identifying and characterizing functional protein sites and compounds for therapeutic development. However, the vast majority of ABPP methods for covalent drug discovery target highly nucleophilic amino acids such as cysteine or lysine. Here, we report a methionine-directed ABPP platform using Redox-Activated Chemical Tagging (ReACT), which leverages a biomimetic oxidative ligation strategy for selective methionine modification. Application of ReACT to oncoprotein cyclin-dependent kinase 4 (CDK4) as a representative high-value drug target identified three new ligandable methionine sites. We then synthesized a methionine-targeting covalent ligand library bearing a diverse array of heterocyclic, heteroatom, and stereochemically rich substituents. ABPP screening of this focused library identified 1oxF11 as a covalent modifier of CDK4 at an allosteric M169 site. This compound inhibited kinase activity in a dose-dependent manner on purified protein and in breast cancer cells. Further investigation of 1oxF11 found prominent cation-π and H-bonding interactions stabilizing the binding of this fragment at the M169 site. Quantitative mass-spectrometry studies validated 1oxF11 ligation of CDK4 in breast cancer cell lysates. Further biochemical analyses revealed cross-talk between M169 oxidation and T172 phosphorylation, where M169 oxidation prevented phosphorylation of the activating T172 site on CDK4 and blocked cell cycle progression. Finally, by identifying a new mechanism for allosteric methionine redox regulation on CDK4 and developing a unique modality for its therapeutic intervention, this work showcases a generalizable platform that provides a starting point for engaging in broader chemoproteomics and protein ligand discovery efforts to find and target previously undruggable methionine sites.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗