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At least 631 records · Page 35
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

Hepatitis C virus NS3/4A inhibitors and other drug-like compounds as covalent binders of SARS-CoV-2 main protease

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), threatens global public health. The world needs rapid development of new antivirals and vaccines to control the current pandemic and to control the spread of the variants. Among the proteins synthesized by the SARS-CoV-2 genome, main protease (M pro also known as 3CL pro ) is a primary drug target, due to its essential role in maturation of the viral polyproteins. In this study, we provide crystallographic evidence, along with some binding assay data, that three clinically approved anti hepatitis C virus drugs and two other drug-like compounds covalently bind to the M pro Cys145 catalytic residue in the active site. Also, molecular docking studies can provide additional insight for the design of new antiviral inhibitors for SARS-CoV-2 using these drugs as lead compounds. One might consider derivatives of these lead compounds with higher affinity to the M pro as potential COVID-19 therapeutics for further testing and possibly clinical trials.

36 MATERIALS SCIENCE↗
DOE OSTI2021

Amino‐Functionalised Hybrid Ultramicroporous Materials that Enable Single‐Step Ethylene Purification from a Ternary Mixture

Abstract Pyrazine‐linked hybrid ultramicroporous (pore size <7 Å) materials (HUMs) offer benchmark performance for trace carbon capture thanks to strong selectivity for CO 2 over small gas molecules, including light hydrocarbons. That the prototypal pyrazine‐linked HUMs are amenable to crystal engineering has enabled second generation HUMs to supersede the performance of the parent HUM, SIFSIX‐3‐Zn , mainly through substitution of the metal and/or the inorganic pillar. Herein, we report that two isostructural aminopyrazine‐linked HUMs, MFSIX‐17‐Ni (17=aminopyrazine; M=Si, Ti), which we had anticipated would offer even stronger affinity for CO 2 than their pyrazine analogs, unexpectedly exhibit reduced CO 2 affinity but enhanced C 2 H 2 affinity. MFSIX‐17‐Ni are consequently the first physisorbents that enable single‐step production of polymer‐grade ethylene (>99.95 % for SIFSIX‐17‐Ni ) from a ternary equimolar mixture of ethylene, acetylene and CO 2 thanks to coadsorption of the latter two gases. We attribute this performance to the very different binding sites in MFSIX‐17‐Ni versus SIFSIX‐3‐Zn .

Mukherjee, Soumya↗
DOE OSTI2021

Amino‐Functionalised Hybrid Ultramicroporous Materials that Enable Single‐Step Ethylene Purification from a Ternary Mixture

Abstract Pyrazine‐linked hybrid ultramicroporous (pore size <7 Å) materials (HUMs) offer benchmark performance for trace carbon capture thanks to strong selectivity for CO 2 over small gas molecules, including light hydrocarbons. That the prototypal pyrazine‐linked HUMs are amenable to crystal engineering has enabled second generation HUMs to supersede the performance of the parent HUM, SIFSIX‐3‐Zn , mainly through substitution of the metal and/or the inorganic pillar. Herein, we report that two isostructural aminopyrazine‐linked HUMs, MFSIX‐17‐Ni (17=aminopyrazine; M=Si, Ti), which we had anticipated would offer even stronger affinity for CO 2 than their pyrazine analogs, unexpectedly exhibit reduced CO 2 affinity but enhanced C 2 H 2 affinity. MFSIX‐17‐Ni are consequently the first physisorbents that enable single‐step production of polymer‐grade ethylene (>99.95 % for SIFSIX‐17‐Ni ) from a ternary equimolar mixture of ethylene, acetylene and CO 2 thanks to coadsorption of the latter two gases. We attribute this performance to the very different binding sites in MFSIX‐17‐Ni versus SIFSIX‐3‐Zn .

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

Deciphering the structure of Arabidopsis thaliana 5-enol-pyruvyl-shikimate-3-phosphate synthase: An essential step toward the discovery of novel inhibitors to supersede glyphosate

Glyphosate interferes with plant aromatic metabolism through the inhibition of 5-enol-pyruvyl-shikimate-3-phosphate (EPSP) synthase [EPSPS, EC 2.5.1.19]. For this reason, EPSPS has been extensively studied in a vast array of organisms. This notwithstanding, up to date, the crystal structure of the protein has been solved exclusively in a few prokaryotes, while that of the plant enzyme has been only deduced in silico by similarity. This study aimed at determining the structure of EPSPS from the plant model species Arabidopsis thaliana, which has been cloned, heterologously expressed and affinity-purified. The kinetic properties of the enzyme have been determined, as well as its susceptibility to the inhibition brought about by glyphosate. The crystal structure of the protein has been resolved at high resolution (1.4 Å), showing open conformation of the enzyme, which is the state ready for substrate/inhibitor binding. This provides a framework for the structure-based design of novel EPSPS inhibitors. Surface regions near the active-site cleft entrance or at the interdomain hinge appear promising for inhibitor selectivity, while bound chloride near the active site is a potential placeholder for anionic moieties of future herbicides.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2025

Energetic and Electronic Properties of UX +/0/– for X = Li and Be and Comparison of the Properties of the Uranium Atom Binding to 2nd Row Elements Li–F

The bonding and spectroscopic properties of ULi +/0/– and UBe +/0/– to complete the series for UX +/0/– for X = Li to F were investigated by high-level ab initio SO-CASPT2 and CCSD(T) electronic structure calculations. The low-lying spin–orbit states were obtained at the SA-CASPT2/aQ-PP level; bond dissociation energies (BDEs), ionization energies (IEs), adiabatic electronic affinities (AEAs), and vertical detachment energies (VDEs) were calculated at the Feller-Peterson-Dixon (FPD) level. A dense manifold of low-lying states was predicted for ULi +/0/– and UBe +/0/– . Here, the calculated BDEs for ULi (37.7 kJ/mol) and UBe (8.0 kJ/mol) show that UBe is weakly bound. For redox processes, the BDEs increased for ULi + (109.3 kJ/mol), ULi – (47.4 kJ/mol), UBe + (35.6 kJ/mol), and UBe – (72.3 kJ/mol). The IE(ULi) = 4.650 eV is lower than IE(Li); the IE(UBe) = 5.901 eV is close to the IE(U) and to the IEs of UB, UC, UN, UO, and UF. The AEAs of ULi (0.708 eV) and UBe (0.989 eV) are lower than those for UB, UC, UN, and UO but higher than that for EA(UF). Natural bond orbital (NBO) calculations show that ULi has the 5f 3 6d 1 7s 2 configuration for U and 2s 1 for Li, with a small partial negative charge slightly delocalized on U. UBe arises from the U(5f 3 6d 1 7s 2 ) and Be(2s 2 ) electron configurations with no charge separation. The same calculations were made for WX (X = Li, Be, C–F) to enable detailed comparisons of the properties for UX with WX (X = Li–F). For WX, BDE(WX) is higher than that for UX for X = Li to N and lower than BDE(UX) for X = O and F, mostly due to the higher IE of W than U as ionic character becomes more important going from Li to F.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗
DOE OSTI2025

Complex Adsorption Behavior of Neodymium and Ytterbium on Structurally-Distinct Alumina Surfaces

New sources of rare earth elements (REEs) are needed to support a green energy transition. REEs adsorbed to aluminum-rich clays in weathering deposits represent important resources but the mechanisms responsible for their retention and ease of extraction are unresolved. Disordered coordination and co-occurrence of multiple species pose challenges to investigating REE adsorption processes via established spectroscopic methods. In this study, we applied element-specific surface crystallography methods to obtain a new perspective on the complexity of REE adsorption mechanisms and affinities. Alumina (001) and (012) crystal surfaces were utilized to evaluate surface-specific controls on Nd(III) and Yb(III) adsorption behavior. The REEs displayed similar total adsorption to alumina (001) as a mixture of inner- and outer-sphere complexes, but Nd displayed a greater proportion of inner-sphere binding. Adsorption of ordered inner- and outer-sphere REE species was substantially lower on alumina (012). These distinct behaviors reflect differences in the surface functional group charging and topography of the two surfaces. However, alumina (012) also hosted a substantial population of disordered adsorbed species, especially for Nd, potentially associated with Al vacancy surface defects. Here, the accumulation of light versus heavy REEs via adsorption in weathering deposits likely results from multiple, competing reactions affected by clay particle morphology. Leaching procedures for resource recovery should account for differential rates of desorption by coexisting inner- and outer-sphere REE surface complexes.

58 GEOSCIENCES↗
DOE OSTI2022

Quantifying the inhibitory impact of soluble phenolics on anaerobic carbon mineralization in a thawing permafrost peatland

The mechanisms controlling the extraordinarily slow carbon (C) mineralization rates characteristic of Sphagnum -rich peatlands (“bogs”) are not fully understood, despite decades of research on this topic. Soluble phenolic compounds have been invoked as potentially significant contributors to bog peat recalcitrance due to their affinity to slow microbial metabolism and cell growth. Despite this potentially significant role, the effects of soluble phenolic compounds on bog peat C mineralization remain unclear. We analyzed this effect by manipulating the concentration of free soluble phenolics in anaerobic bog and fen peat incubations using water-soluble polyvinylpyrrolidone (“PVP”), a compound that binds with and inactivates phenolics, preventing phenolic-enzyme interactions. CO 2 and CH 4 production rates (end-products of anaerobic C mineralization) generally correlated positively with PVP concentration following Michaelis-Menten (M.M.) saturation functions. Using M.M. parameters, we estimated that the extent to which phenolics inhibit anaerobic CO 2 production was significantly higher in the bog—62 ± 16%—than the fen—14 ± 4%. This difference was found to be more substantial with regards to methane production—wherein phenolic inhibition for the bog was estimated at 54 ± 19%, while the fen demonstrated no apparent inhibition. Consistent with this habitat difference, we observed significantly higher soluble phenolic content in bog vs. fen pore-water. Together, these findings suggest that soluble phenolics could contribute to bogs’ extraordinary recalcitrance and high (relative to other peatland habitats) CO 2 :CH 4 production ratios.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1988

Two puzzling aspects of protein crystal growth

A study is presented of several mechanisms which may reduce crystal growth rates and or terminate crystal growth. It is found that salt gradients which change the local chemical potential of the protein are insufficient to account for the slow crystal growth rates which have been reported. Contaminants which adsorb protein from solution may reduce the effective protein concentration, but the impurity's concentration and its affinity for protein are unknown. Association of protein molecules in bulk solution can reduce the monomer concentration significantly, but extant theory and experiment are not sensitive enough to determine the actual concentration of aggregates in solution. For systems of interest, shear-induced effects were found to be too weak to interfere with normal binding of incoming protein molecules. Although we found that most crystal growth occurs in a regime where both interfacial kinetics and diffusion influence crystal growth, the role of mass transfer rates on the terminal size of crystals is unknown, primarily because no data exist which cover the size range of interest (0.1 mm to 1 mm in length).

Grant, M. L.↗
DOE OSTI2020

Surface Ligands for Methylammonium Lead Iodide Films: Surface Coverage, Energetics, and Photovoltaic Performance

Surface ligand treatment provides a promising approach for passivating defect states, improving material and device stability, manipulating interfacial energetics, and improving the performance of perovskite solar cells (PSCs). To facilitate targeted selection and design of surface ligands for PSCs, it is necessary to establish relationships between ligand structure and perovskite surface properties. In this work, surface ligands with different binding groups are investigated to determine their extent of surface coverage, whether they form a surface monolayer or penetrate the perovskite, how they influence material energetics and photoluminescence, and how this combination of factors affects PSC performance. Ultraviolet and inverse photoelectron spectroscopy measurements show that surface ligands can significantly shift the ionization energy and electron affinity. Lastly, these changes in surface energetics substantially impact PSC performance, with the performance decreasing for ligands that create less favorable energy landscapes for electron transfer from MAPbI 3 to the electron transport layer, C 60 .

14 SOLAR ENERGY↗
DOE OSTI2023

MXene Nanosheets Functionalized with Cu Atoms for Urea Adsorption in Aqueous Media

Ti 3 C 2 T x MXene is an emerging family of two-dimensional materials, and because of its large specific surface area, it has potential for many applications. Herein, a new application using Cu-doped MILD (minimally intensive layer delamination) synthesized Ti 3 C 2 T x MXene for urea removal is demonstrated. The doping of Cu on MXene results in an increase in its affinity for urea adsorption as compared to the pristine MILD synthesized MXene due to the formation of the Cu–urea complex. Previous computational studies have shown that the adsorption energies of urea on the MXene surface can be improved in the presence of Cu. The valence state of Cu in the doped MILD synthesized MXene, which binds on to the surface via Ti–O–Cu linkage, is between 0 and +1 as verified by XAS and XPS. As the optimal urea adsorption occurs on Cu as a single atom site, an increase in Cu doping on MXene does not increase urea removal due to Cu agglomeration. Furthermore, looking at the adsorption behaviour, it seems that Cu-doped MXene follows the monolayer adsorption on homogenous surface model.

36 MATERIALS SCIENCE↗
DOE OSTI2025

Computational design of potent and selective binders of BAK and BAX

Potent and selective binders of the key proapoptotic proteins BAK and BAX have not been described. We use computational protein design to generate high affinity binders of BAK and BAX with greater than 100-fold specificity for their target. Both binders activate their targets when at low concentration, driving pore formation, but inhibit membrane permeabilization when in excess. Crystallography shows that the BAK binder induces BAK unfolding, exposing the α6 helix and BH3 domain. Together, these data suggest that upon binding, BAK or BAX unfold; at high binder concentrations, self-association of the partially folded BAK or BAX proteins is blocked and the membrane remains intact, whereas at low concentrations, dimers form, and the membrane ruptures. Our designed binders modulate apoptosis via direct, specific interactions with BAK and BAX and reveal that for therapeutic strategies targeting BAK and BAX, inhibition requires saturating binder concentrations at the site of action.

Berger, Stephanie↗
DOE OSTI2025

Precision Labeling of Native Antibodies with Lock Coupling

The formation of stable protein complexes enables much of biotechnology, but even high-affinity complexes can dissociate, limiting potential applications in biomaterials, bioimaging, nanomedicine, and other protein-based technologies. Here, in this study, we describe lock coupling, a simple and selective one-step reaction between interfacial lysine and glutamate or aspartate side chains to form stable isopeptide bonds and be used for the precise labeling of native antibodies. We identify conditions in which short-lived activated esters formed by the aqueous carbodiimide EDC promote isopeptide bond formation specifically at preassociated amine-acid pairs. Indiscriminate cross-linking is minimized by formation of protein complexes before addition of catalyst, use of acidic pH to suppress exposed Lys reactivity, and limiting the aqueous stability of activated esters. For native antibody (Ab) labeling, we show that the small IgG-binding protein GB1 can be covalently attached to the Ab Fc domain and that introduction of Cys into GB1 loops allows for facile conjugation of fluorophores, micelles, or inorganic nanocrystals for imaging in live cells and animals. By varying Cys substituents and protein stoichiometry, a defined number of probes can be uniformly attached without the need for extensive purification. In live-cell confocal microscopy, labeled GB1 serves as a stable replacement for secondary Abs, enabling simple multicolor immunostaining and imaging. Lock coupling requires just a single reagent in aqueous buffer and leverages both the innate ability of proteins to form high-affinity complexes and the widespread presence of Lys-Glu/Asp pairs at their interfaces, with the potential for precision synthesis of protein-based probes for imaging, biomaterials, biophysics, and medicine.

antibody↗
DOE OSTI2023

Shark nanobodies with potent SARS-CoV-2 neutralizing activity and broad sarbecovirus reactivity

Despite rapid and ongoing vaccine and therapeutic development, SARS-CoV-2 continues to evolve and evade, presenting a need for next-generation diverse therapeutic modalities. Here we show that nurse sharks immunized with SARS-CoV-2 recombinant receptor binding domain (RBD), RBD-ferritin (RFN), or spike protein ferritin nanoparticle (SpFN) immunogens elicit a set of new antigen receptor antibody (IgNAR) molecules that target two non-overlapping conserved epitopes on the spike RBD. Representative shark antibody variable NAR-Fc chimeras (ShAbs) targeting either of the two epitopes mediate cell-effector functions, with high affinity to all SARS-CoV-2 viral variants of concern, including the divergent Omicron strains. The ShAbs potently cross-neutralize SARS-CoV-2 WA-1, Alpha, Beta, Delta, Omicron BA.1 and BA.5, and SARS-CoV-1 pseudoviruses, and confer protection against SARS-CoV-2 challenge in the K18-hACE2 transgenic mouse model. Structural definition of the RBD-ShAb01-ShAb02 complex enabled design and production of multi-specific nanobodies with enhanced neutralization capacity, and picomolar affinity to divergent sarbecovirus clade 1a, 1b and 2 RBD molecules. These shark nanobodies represent potent immunotherapeutics both for current use, and future sarbecovirus pandemic preparation.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2020

Mutations in penicillin-binding protein 2 from cephalosporin-resistant Neisseria gonorrhoeae hinder ceftriaxone acylation by restricting protein dynamics

The global incidence of the sexually transmitted disease gonorrhea is expected to rise due to the spread of Neisseria gonorrhoeae strains with decreased susceptibility to extended-spectrum cephalosporins (ESCs). ESC resistance is conferred by mosaic variants of penicillin-binding protein 2 (PBP2) that have diminished capacity to form acylated adducts with cephalosporins. To elucidate the molecular mechanisms of ESC resistance, we conducted a biochemical and high-resolution structural analysis of PBP2 variants derived from the decreased-susceptibility N. gonorrhoeae strain 35/02 and ESC-resistant strain H041. Our data reveal that mutations both lower affinity of PBP2 for ceftriaxone and restrict conformational changes that normally accompany acylation. Specifically, we observe that a G545S substitution hinders rotation of the β3 strand necessary to form the oxyanion hole for acylation and also traps ceftriaxone in a noncanonical configuration. In addition, F504L and N512Y substitutions appear to prevent bending of the β3–β4 loop that is required to contact the R1 group of ceftriaxone in the active site. Other mutations also appear to act by reducing flexibility in the protein. Overall, our findings reveal that restriction of protein dynamics in PBP2 underpins the ESC resistance of N. gonorrhoeae.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

A new class of antibodies that overcomes a steric barrier to cross-group neutralization of influenza viruses

Antibody titers that inhibit the influenza virus hemagglutinin (HA) from engaging its receptor are the accepted correlate of protection from infection. Many potent antibodies with broad, intra-subtype specificity bind HA at the receptor binding site (RBS). One barrier to broad H1-H3 cross-subtype neutralization is an insertion (133a) between positions 133 and 134 on the rim of the H1 HA RBS. We describe here a class of antibodies that overcomes this barrier. These genetically unrestricted antibodies are abundant in the human B cell memory compartment. Analysis of the affinities of selected members of this class for historical H1 and H3 isolates suggest that they were elicited by H3 exposure and broadened or diverted by later exposure(s) to H1 HA. RBS mutations in egg-adapted vaccine strains cause the new H1 specificity of these antibodies to depend on the egg adaptation. The results suggest that suitable immunogens might elicit 133a-independent, H1-H3 cross neutralization by RBS-directed antibodies.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2017

BioWires: Conductive DNA Nanowires in a Computationally-Optimized, Synthetic Biological Platform for Nanoelectronic Fabrication

DNA is an ideal template for a biological nanowire-it has a linear structure several atoms thick; it possesses addressable nucleobase geometry that can be precisely defined; and it is massively scalable into branched networks. Until now, the drawback of DNA as a conducting nanowire been, simply put, its low conductance. To address this deficiency, we extensively characterize a chemical variant of canonical DNA that exploits the affinity of natural cytosine bases for silver ions. We successfully construct chains of single silver ions inside double-stranded DNA, confirm the basic dC-Ag+-dC bond geometry and kinetics, and show length-tunability dependent on mismatch distribution, ion availability and enzyme activity. An analysis of the absorbance spectra of natural DNA and silver-binding, poly-cytosine DNA demonstrates the heightened thermostability of the ion chain and its resistance to aqueous stresses such as precipitation, dialysis and forced reduction. These chemically critical traits lend themselves to an increase in electrical conductivity of over an order of magnitude for 11-base silver-paired duplexes over natural strands when assayed by STM break junction. We further construct and implement a genetic pathway in the E. coli bacterium for the biosynthesis of highly ionizable DNA sequences. Toward future circuits, we construct a model of transcription network architectures to determine the most efficient and robust connectivity for cell-based fabrication, and we perform sequence optimization with a genetic algorithm to identify oligonucleotides robust to changes in the base-pairing energy landscape. We propose that this system will serve as a synthetic biological fabrication platform for more complex DNA nanotechnology and nanoelectronics with applications to deep space and low resource environments.

DNA↗
DOE OSTI2020

Determinants for proton location and electron coupled proton transfer in hydrogen bonded pentafluorophenol-anion clusters

This work aims to reveal the determinant factors for proton locations and electron coupled proton transfer (ECPT) in biologically relevant hydrogen bonded systems. Pentafluorophenol-anion clusters [C6F5O-•H+•A-]- are chosen to model active sites of biological functions, with the anion A- being systematically varied to ensure the proton affinities (PAs) of the anions well cover the referenced PA of C6F5O- from being appreciably smaller, similar, and to significantly larger. Negative ion photoelectron spectroscopy of these clusters provides spectroscopic evidence showing that proton location in the anionic state is largely following the PA prediction, while ECPT is observed only for the clusters with the anion possessing the electron binding energy (EBE) significantly larger than that of the referenced C6F5O-. Theoretical calculations suggest these clusters are stabilized by forming single strong hydrogen bond between donor and acceptor, and the associated charge and MO analyses fully support the experimental observations. The current holistic cluster model study indicates that PA is the right determinant that can be used to predict the proton location and describe hydrogen bonding structures, while both PA and EBE of anionic groups play important roles in facilitating ECPT process. This work was supported by U.S. Department of Energy (DOE), Office of Basic Energy Sciences, Division of Chemical Science, Geosciences, and Biosciences (X.-B.W.), and performed using EMSL, a national scientific user facility sponsored by DOE’s Office of Biological and Environmental Research and located at Pacific Northwest National Laboratory, which is operated by Battelle Memorial Institute for the DOE. Part of this work was supported by the National Natural Science Foundation of China (No-11604046 for JZ; No. 11727810 for ZRS), as well as “Chenguang Program” by Shanghai Education Development Foundation, Shanghai Municipal Education Commission (No. 16CG38) and Natural Science Foundation of Shanghai (No. 16ZR1448100) (JZ).

Zhang, Jian↗