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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 505 records · Page 28

A combination of cross-neutralizing antibodies synergizes to prevent SARS-CoV-2 and SARS-CoV pseudovirus infection

Coronaviruses have caused several human epidemics and pandemics including the ongoing coronavirus disease 2019 (COVID-19). Prophylactic vaccines and therapeutic antibodies have already shown striking effectiveness against COVID-19. Nevertheless, concerns remain about antigenic drift in SARS-CoV-2 as well as threats from other sarbecoviruses. Cross-neutralizing antibodies to SARS-related viruses provide opportunities to address such concerns. Here, we report on crystal structures of a cross-neutralizing antibody, CV38-142, in complex with the receptor-binding domains from SARS-CoV-2 and SARS-CoV. Recognition of the N343 glycosylation site and water-mediated interactions facilitate cross-reactivity of CV38-142 to SARS-related viruses, allowing the antibody to accommodate antigenic variation in these viruses. CV38-142 synergizes with other cross-neutralizing antibodies, notably COVA1-16, to enhance neutralization of SARS-CoV and SARS-CoV-2, including circulating variants of concern B.1.1.7 and B.1.351. Overall, this study provides valuable information for vaccine and therapeutic design to address current and future antigenic drift in SARS-CoV-2 and to protect against zoonotic SARS-related coronaviruses.

3D structure↗

The reactive flow evolution of the polymer-bonded explosive PBX 9502: Experiments and model validation in extreme pressure regimes

The shock-to-detonation transition properties of the triaminotrinitrobenzene based PBX 9502 high explosive (HE) are experimentally and computationally explored in extremely high input pressure conditions. These include both slightly sub-Chapman–Jouguet and overdriven input pressure conditions, namely, ∼25 and ∼31 GPa, respectively. Our experiments capture the transient buildup of a shock-induced reaction via measurement of HE and polymethyl methacrylate window interface particle velocity profiles for a variety of sample thicknesses for this insensitive HE. These observations necessitate extremely thin explosive samples, and the high rates of reaction provide a considerable challenge to optical diagnostics. Samples at these thicknesses also provide an opportunity for evaluation of potential micro-structure effects on the resulting shock-to-detonation-transition measurements. To address this, the thin samples are also characterized via x-ray micro-computed tomography. Finally, a pair of previously established continuum-level detonation performance modeling approaches for PBX 9502 were used to analyze the experiments. The employed model variants crucially differ in their definition of each model’s empirical reaction rate functional form, utilization of shock state quantities, and local flow variable dependencies. As a result, the present experiments provide a novel platform to evaluate the quantitative and qualitative consequences stemming from these modeling choices in a challenging initiation scenario, largely beyond the chosen calibration range of either model. This new experimental information will provide a platform for both improved physics and model parameterizations for this well-studied explosive.

36 MATERIALS SCIENCE↗

A New Approach to Distributed Hypothesis Testing and Non-Bayesian Learning: Improved Learning Rate and Byzantine-Resilience

Here, we study a setting where a group of agents, each receiving partially informative private signals, seek to collaboratively learn the true underlying state of the world (from a finite set of hypotheses) that generates their joint observation profiles. To solve this problem, we propose a distributed learning rule that differs fundamentally from existing approaches, in that it does not employ any form of “belief-averaging”. Instead, agents update their beliefs based on a min-rule. Under standard assumptions on the observation model and the network structure, we establish that each agent learns the truth asymptotically almost surely. As our main contribution, we prove that with probability 1, each false hypothesis is ruled out by every agent exponentially fast, at a network-independent rate that is strictly larger than existing rates. We then develop a computationally-efficient variant of our learning rule that is provably resilient to agents who do not behave as expected (as represented by a Byzantine adversary model) and deliberately try to spread misinformation.

42 ENGINEERING↗

A Prevalent Focused Human Antibody Response to the Influenza Virus Hemagglutinin Head Interface

Novel animal influenza viruses emerge, initiate pandemics, and become endemic seasonal variants that have evolved to escape from prevalent herd immunity. These processes often outpace vaccine-elicited protection. Focusing immune responses on conserved epitopes may impart durable immunity. We describe a focused, protective antibody response, abundant in memory and serum repertoires, to a conserved region at the influenza virus hemagglutinin (HA) head interface. Structures of 11 examples, 8 reported here, from seven human donors demonstrate the convergence of responses on a single epitope. The 11 are genetically diverse, with one class having a common, IGκV1-39, light chain. All of the antibodies bind HAs from multiple serotypes. The lack of apparent genetic restriction and potential for elicitation by more than one serotype may explain their abundance. We define the head interface as a major target of broadly protective antibodies with the potential to influence the outcomes of influenza virus infection.

60 APPLIED LIFE SCIENCES↗

Quantum Chemical Computation of Omicron Mutations Near Cleavage Sites of the Spike Protein

The attachment of the spike protein in SARS-CoV-2 to host cells and the initiation of viral invasion are two critical processes in the viral infection and transmission in which the presence of unique furin (S1/S2) and TMPRSS2 (S2') cleavage sites play a pivotal role. We provide a detailed analysis of the impact of the BA.1 Omicron mutations vicinal to these cleavage sites using a novel computational method based on the amino acid–amino acid bond pair unit (AABPU), a specific protein structural unit as a proxy for quantifying the atomic interaction. Our study is focused mainly on the spike region between subdomain 2 (SD2) and the central helix (CH), which contains both S1/S2 and S2' cleavage sites. Based on ab initio quantum calculations, we have identified several key features related to the electronic structure and bonding of the Omicron mutations that significantly increase the size of the relevant AABPUs and the positive charge. These findings enable us to conjecture on the biological role of Omicron mutations and their specific effects on cleavage sites and identify the principles that can be of some value in analyzing new variants.

60 APPLIED LIFE SCIENCES↗

Time-periodic steady-state solution of fluid-structure interaction and cardiac flow problems through multigrid-reduction-in-time

In this study, a time-periodic MGRIT algorithm is proposed as a means to reduce the time-to-solution of numerical algorithms by exploiting the time periodicity inherent to many applications in science and engineering. The time-periodic MGRIT algorithm is applied to a variety of linear and nonlinear single- and multiphysics problems that are periodic-in-time. It is demonstrated that the proposed parallel-in-time algorithm can obtain the same time-periodic steady-state solution as sequential time-stepping. It is shown that the required number of MGRIT iterations can be estimated a priori and that the new MGRIT variant can significantly and consistently reduce the time-to-solution compared to sequential time-stepping, irrespective of the number of dimensions, linear or nonlinear PDE models, single-physics or coupled problems and the employed computing resources. The numerical experiments demonstrate that the time-periodic MGRIT algorithm enables a greater level of parallelism yielding faster turnaround, and thus, facilitating more complex and more realistic problems to be solved.

97 MATHEMATICS AND COMPUTING↗

Combining computational modeling and experimental library screening to affinity-mature VEEV-neutralizing antibody F5

Engineered monoclonal antibodies have proven to be highly effective therapeutics in recent viral outbreaks. However, despite technical advancements, an ability to rapidly adapt or increase antibody affinity and by extension, therapeutic efficacy, has yet to be fully realized. We endeavored to stand-up such a pipeline using molecular modeling combined with experimental library screening to increase the affinity of F5, a monoclonal antibody with potent neutralizing activity against Venezuelan Equine Encephalitis Virus (VEEV), to recombinant VEEV (IAB) E1E2 antigen. We modeled the F5/E1E2 binding interface and generated predictions for mutations to improve binding using a Rosetta-based approach and dTERMen, an informatics approach. The modeling was complicated by the fact that a high-resolution structure of F5 is not available and the H3 loop of F5 exceeds the length for which current modeling approaches can determine a unique structure. A subset of the predicted mutations from both methods were incorporated into a phage display library of scFvs. This library and a library generated by error-prone PCR were screened for binding affinity to the recombinant antigen. Results from the screens identified favorable mutations which were incorporated into 12 human-IgG1 variants. The best variant, containing eight mutations, improved KD from 0.63 nM (parental) to 0.01 nM. While this did not improve neutralization or therapeutic potency of F5 against IAB, it did increase cross-reactivity to other closely related VEEV epizootic and enzootic strains, demonstrating the potential of this method to rapidly adapt existing therapeutics to emerging viral strains.

affinity-maturation↗

Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD

Neutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitopedependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCsandmediatestrong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinantsoftheepitope-drivenprotectionandVOCevasion.WhileEH3represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 micefrom lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients.

60 APPLIED LIFE SCIENCES↗

Triple Excitations in Green’s Function Coupled Cluster Solver for Studies of Strongly Correlated Systems in the Framework of Self-Energy Embedding Theory

Embedding theories became important approaches used for accurate calculations of both molecules and solids. In these theories, a small chosen subset of orbitals is treated with an accurate method, called an impurity solver, capable of describing higher correlation effects. Ideally, such a chosen fragment should contain multiple orbitals responsible for the chemical and physical behavior of the compound. Handling a large number of chosen orbitals presents a very significant challenge for the current generation of solvers used in the physics and chemistry community. Here, we develop a Green’s function coupled cluster singles doubles and triples (GFCCSDT) solver that can be used for a quantitative description in both molecules and solids. This solver allows us to treat orbital spaces that are inaccessible to other accurate solvers. At the same time, GFCCSDT maintains high accuracy of the resulting self-energy. Moreover, in conjunction with the GFCCSD solver, it allows us to test the systematic convergence of computational studies. Developing the CC family of solvers paves the road to fully systematic Green’s function embedding calculations in solids. In this paper, we focus on the investigation of GFCCSDT self-energies for a strongly correlated problem of SrMnO 3 solid. Subsequently, we apply this solver to solid MnO showing that an approximate variant of GFCCSDT is capable of yielding a high accuracy orbital resolved spectral function.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

A variant of the MenB strain of Synechocystis sp. PCC 6803 disrupts a stress response pathway allowing DMPBQ to occupy the A 1 sites of photosystem I

Phylloquinone (PhQ) plays a unique role in photosynthesis as the A1A and A1B intermediates in light-driven electron transfer in Photosystem I (PSI). When PhQ biosynthesis is inhibited by deletion of the menB gene in the cyanobacterium Synechocystis sp. PCC 6803, previous studies have shown that plastoquinone-9 (PQ-9) occupies the A 1 sites. However, a recent cryo-electron microscopy structure of a strain of ΔmenB from the year 2023 revealed an unusual quinone in the A 1 sites with a benzoquinone headgroup similar to PQ-9 and a phytyl tail similar to PhQ. Here, we investigate its biosynthesis and binding properties. Mass spectrometry confirms that PSI from the 2023 ΔmenB strain contains 2,3-dimethyl-5-phytyl-1,4-benzoquinone (DMPBQ), while PSI from the original strain contains PQ-9. Whole genome sequencing reveals that a mutation in slr1737 (tocopherol cyclase) leads to the accumulation of DMPBQ, an intermediate in the tocopherol biosynthetic pathway. Transient optical and electron paramagnetic resonance spectroscopy studies show that when DMPBQ occupies the A 1 sites, it does not exchange with exogenously supplied PhQ in contrast to PQ-9, which exchanges readily. We propose that the slr1737 mutation in the 2023 ΔmenB strain is a likely candidate for the source of the phenotype. This new strain has sacrificed tocopherol synthesis, the absence of which is known to have no effect on growth under low stress conditions, resulting in incorporation of DMPBQ in the A 1 sites. The tighter binding and function of DMPBQ likely allow this ΔmenB strain to outcompete its peers under optimal growth conditions and thus dominate the population.

2,3-dimethyl-5-phytyl-1,4-benzoquinone↗

Network analysis uncovers the communication structure of SARS-CoV-2 spike protein identifying sites for immunogen design

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has triggered myriad efforts to understand the structure and dynamics of this complex pathogen. The spike glycoprotein of SARS-CoV-2 is a significant target for immunogens as it is the means by which the virus enters human cells, while simultaneously sporting mutations responsible for immune escape. These functional and escape processes are regulated by complex molecular-level interactions. Our study presents quantitative insights on domain and residue contributions to allosteric communication, immune evasion, and local- and global-level control of functions through the derivation of a weighted graph representation from all-atom MD simulations. Focusing on the ancestral form and the D614G-variant, we provide evidence of the utility of our approach by guiding the selection of a mutation that alters the spike’s stability. Taken together, the network approach serves as a valuable tool to evaluate communication “hot-spots” in proteins to guide design of stable immunogens.

60 APPLIED LIFE SCIENCES↗

The Story of 5d Metallocorroles: From Metal–Ligand Misfits to New Building Blocks for Cancer Phototherapeutics

Porphyrin chemistry is Shakespearean: over a century of study has not withered the field’s apparently infinite variety. Heme proteins continually astonish us with novel molecular mechanisms, while new porphyrin analogues bowl us over with unprecedented optical, electronic, and metal-binding properties. Within the latter domain, corroles occupy a special place, exhibiting a unique and rich coordination chemistry. The 5d metallocorroles are arguably the icing on that cake. New Zealand chemist Penny Brothers has used the word “misfit” to describe the interactions of boron, a small atom with a predilection for tetrahedral coordination, and porphyrins, classic square-planar ligands. Steve Jobs lionized misfits as those who see things differently and push humanity forward. Both perspectives have inspired us. The 5d metallocorroles are misfits in that they encapsulate a large 5d transition metal ion within the tight cavity of a contracted porphyrin ligand. Given the steric mismatch inherent in their structures, the syntheses of some 5d metallocorroles are understandably capricious, proceeding under highly specific conditions and affording poor yields. Three broad approaches may be distinguished. (a) In the metal–alkyl approach, a free-base corrole is exposed to an alkyllithium and the resulting lithio-corrole is treated with an early transition metal chloride; a variant of the method eschews alkyllithium and deploys a transition metal–alkyl instead, resulting in elimination of the alkyl group as an alkane and insertion of the metal into the corrole. This approach is useful for inserting transition metals from groups 4, 5, and, to some extent, 6, as well as lanthanides and actinides. (b) In our laboratory, we have often deployed a low-valent organometallic approach for the middle transition elements (groups 6, 7, 8, and 9). The reagents are low-valent metal–carbonyl or −olefin complexes, which lose one or more carbon ligands at high temperature, affording coordinatively unsaturated, sticky metal fragments that are trapped by the corrole nitrogens. (c) Finally, a metal acetate approach provides the method of choice for gold and platinum insertion (groups 10 and 11). This Account provides a first-hand perspective of the three approaches, focusing on the last two, which were largely developed in our laboratory. In general, the products were characterized with X-ray crystallography, electrochemistry, and a variety of spectroscopic methods. The physicochemical data, supplemented by relativistic DFT calculations, have provided fascinating insights into periodic trends and relativistic effects. An unexpected feature of many 5d metallocorroles, given their misfit character, is their remarkable stability under thermal, chemical, and photochemical stimulation. Many of them also exhibit long triplet lifetimes on the order of 100 μs and effectively sensitize singlet oxygen formation. Many exhibit phosphorescence in the near-infrared under ambient conditions. Furthermore, water-soluble ReO and Au corroles exhibit impressive photocytotoxicity against multiple cancer cell lines, promising potential applications as cancer phototherapeutics. We thus envision a bright future for the compounds as rugged building blocks for new generations of therapeutic and diagnostic (theranostic) agents.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Expanding the substrate scope of pyrrolysyl-transfer RNA synthetase enzymes to include non-$α$-amino acids in vitro and in vivo

The absence of orthogonal aminoacyl-transfer RNA (tRNA) synthetases that accept non-L-α-amino acids is a primary bottleneck hindering the in vivo translation of sequence-defined hetero-oligomers and biomaterials. Here we report that pyrrolysyl-tRNA synthetase (PylRS) and certain PylRS variants accept α-hydroxy, α-thio and N-formyl-L-α-amino acids, as well as α-carboxy acid monomers that are precursors to polyketide natural products. These monomers are accommodated and accepted by the translation apparatus in vitro; those with reactive nucleophiles are incorporated into proteins in vivo. High-resolution structural analysis of the complex formed between one PylRS enzyme and a m-substituted 2-benzylmalonic acid derivative revealed an active site that discriminates prochiral carboxylates and accommodates the large size and distinct electrostatics of an α-carboxy substituent. This work emphasizes the potential of PylRS-derived enzymes for acylating tRNA with monomers whose α-substituent diverges substantially from the α-amine of proteinogenic amino acids. These enzymes or derivatives thereof could synergize with natural or evolved ribosomes and/or translation factors to generate diverse sequence-defined non-protein heteropolymers.

59 BASIC BIOLOGICAL SCIENCES↗

Understanding the phase transformation mechanisms that affect the dynamic response of Fe-based microstructures at the atomic scales

Large-scale molecular dynamics (MD) simulations were carried out to investigate the shock-induced evolution of microstructure in Fe-based systems comprising single-crystal and layered Cu/Fe alloys with a distribution of interfaces. The shock compression of pure single-crystal Fe oriented along [110] above a threshold pressure results in a BCC (α)→HCP (ε) phase transformation behavior that generates a distribution of ε phase variants in the phase transformed region of the microstructure behind the shock front. The propagation of the release wave through a phase transformed ε phase causes a reverse ε→α phase transformation and renders a distribution of twins for the [110] oriented Fe that serve as void nucleation sites during spall failure. The simulations reveal that the α→ε→α transformation-induced twinning for shock loading along the [110] direction is due to a dominant ε phase variant formed during compression that rotates on the arrival of the release wave followed by a reverse phase transformation to twins in the α phase. The modifications in the evolution of the ε phase variants and twins in Fe behavior are also studied for Cu–Fe layered microstructures due to the shock wave interactions with the Cu/Fe interfaces using a newly constructed Cu–Fe alloy potential. Here, the MD simulations suggest that interfaces affect the observed variants during shock compression and, hence, distributions of twins during shock release that affects the void nucleation stresses in the Fe phase of Cu/Fe microstructures.

36 MATERIALS SCIENCE↗

Characterization of SETD3 methyltransferase–mediated protein methionine methylation

Most characterized protein methylation events encompass arginine and lysine N-methylation, and only a few cases of protein methionine thiomethylation have been reported. Newly discovered oncohistone mutations include lysine-to-methionine substitutions at positions 27 and 36 of histone H3.3. In these cases, the methionine substitution localizes to the active-site pocket of the corresponding histone lysine methyltransferase, thereby inhibiting the respective transmethylation activity. SET domain–containing 3 (SETD3) is a protein (i.e. actin) histidine methyltransferase. Here, we generated an actin variant in which the histidine target of SETD3 was substituted with methionine. As for previously characterized histone SET domain proteins, the methionine substitution substantially (76-fold) increased binding affinity for SETD3 and inhibited SETD3 activity on histidine. Unexpectedly, SETD3 was active on the substituted methionine, generating S-methylmethionine in the context of actin peptide. The ternary structure of SETD3 in complex with the methionine-containing actin peptide at 1.9 Å resolution revealed that the hydrophobic thioether side chain is packed by the aromatic rings of Tyr 312 and Trp 273 , as well as the hydrocarbon side chain of Ile 310 . Our results suggest that placing methionine properly in the active site—within close proximity to and in line with the incoming methyl group of SAM—would allow some SET domain proteins to selectively methylate methionine in proteins.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Structure of a Vaccine-Induced, Germline-Encoded Human Antibody Defines a Neutralizing Epitope on the SARS-CoV-2 Spike N-Terminal Domain

Structural characterization of infection- and vaccination-elicited antibodies in complex with antigen provides insight into the evolutionary arms race between the host and the pathogen and informs rational vaccine immunogen design. We isolated a germ line-encoded monoclonal antibody (mAb) from plasmablasts activated upon mRNA vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and determined its structure in complex with the spike glycoprotein by electron cryomicroscopy (cryo-EM). We show that the mAb engages a previously uncharacterized neutralizing epitope on the spike N-terminal domain (NTD). The high-resolution structure reveals details of the intermolecular interactions and shows that the mAb inserts its heavy complementarity-determining region 3 (HCDR3) loop into a hydrophobic NTD cavity previously shown to bind a heme metabolite, biliverdin. We demonstrate direct competition with biliverdin and that, because of the conserved nature of the epitope, the mAb maintains binding to viral variants B.1.1.7 (alpha), B.1.351 (beta), B.1.617.2 (delta), and B.1.1.529 (omicron). Our study describes a novel conserved epitope on the NTD that is readily targeted by vaccine-induced antibody responses.

59 BASIC BIOLOGICAL SCIENCES↗

Substituent size versus metal binding of inhibitors with variants of influenza endonuclease

The influenza virus causes a significant burden of illness each year. Although vaccination is the most effective method to prevent seasonal influenza infection, viral escape mechanisms make vaccine composition difficult to predict. Antivirals are crucial for decreasing rates of morbidity and mortality from influenza viral infection. The newest anti-influenza drugs target the RNA-dependent RNA polymerase acidic N-terminal (PA N ) endonuclease, a critical component of influenza viral replication machinery. This study examines the structure of inhibitors of PAN that utilize a hydroxypyridinone-based metal-binding pharmacophore (MBP). Specifically, this report explores how the size of substituent groups impacts the binding conformation and affinity of a series of compounds against both wild-type (WT) and resistance mutant strains, I38T and E23K. Co-crystal structures revealed that the distance between compounds and enzyme residue 38 was conserved to maintain strong interactions, resulting in deviations from ideal coordination geometries at the active site metal centers. This suggests the interactions with residue 38 with each compound is important and can impact inhibitor potency as a consequence of distortions in the metal binding geometry of the compounds.

Endonuclease↗

Linking Domain Structure Evolution at a Grain Boundary to Piezoelectric Response via Nano‐Diffraction

Electric-field-induced domain structure switching in a 1 𝜇⁢m -thick Pb 0.99 (Zr 0.45 Ti 0.55 ) 0.98 Nb 0.02 O 3 (Nb-doped PZT) bicrystal film was characterized in situ via nano-focused synchrotron diffraction. The epitaxial film was deposited on a (100) SrTiO 3 bicrystal substrate. The changes in domain structure were mapped within a 5 𝜇⁢m × 5 𝜇⁢m area at and around an in-plane tilt-type (23.6°) grain boundary with 50 nm spatial resolution. Rocking curves collected at each point of the mapped area provided the ability to reconstruct spatially-varying three-dimensional (3D) reciprocal space maps around the grain boundary. The 3D reciprocal space maps reveal how different tilted 𝑎 -type domain variants interact with the grain boundary as a function of increasing electric field. Initially, a subset of 𝑎 -type domain variants with their polarization vectors largely orthogonal to the grain boundary were found in greater abundance within 570 nm of the grain boundary, possibly due to X-ray beam-induced local increases in the electrical conductivity, but after the coercive field was exceeded, reconfiguration of the ferroelastic domains was observed. The spatially-varying reciprocal space maps also facilitated evaluation of the strain field across the mapped area, along with 𝑑 33,𝑓 . Significant spatial heterogeneity of strain and 𝑑 33,𝑓 are observed, especially at the coercive field, which was attributed to maintaining deformation compatibility and correlated ferroelastic switching.

36 MATERIALS SCIENCE↗