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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 1,549 records · Page 86
All sourcesNASA NTRSDOE OSTI
DOE OSTI2021

Structural basis for SARS-CoV-2 envelope protein recognition of human cell junction protein PALS1

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created global health and economic emergencies. SARS-CoV-2 viruses promote their own spread and virulence by hijacking human proteins, which occurs through viral protein recognition of human targets. To understand the structural basis for SARS-CoV-2 viral-host protein recognition, here we use cryo-electron microscopy (cryo-EM) to determine a complex structure of the human cell junction protein PALS1 and SARS-CoV-2 viral envelope (E) protein. Our reported structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains of PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce E-mediated virulence.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2017

Local structure of liquid gallium under pressure

In situ high energy X-ray pair distribution function (PDF) measurements, microtomography and reverse Monte Carlo simulations were used to characterize the local structure of liquid gallium up to 1.9 GPa. This pressure range includes the well-known solid-solid phase transition from Ga-I to Ga-II at low temperature. In term of previous research, the local structure of liquid gallium within this domain was suggested a mixture of two local structures, Ga I and Ga II, based on fitting experimental PDF to known crystal structure, with a controversy. However, our result shows a distinctly different result that the local structure of liquid gallium resembles the atomic arrangement of both gallium phase II and III (the high pressure crystalline phase). A melting mechanism is proposed for Ga, in which the atomic structure of phase Ι breaks up at the onset of melting, providing sufficient free volume for atoms to rearrange, to form the melt.

Science & Technology - Other Topics↗
DOE OSTI2024

Dynamic structural determinants in bacterial microcompartment shells

Bacterial microcompartments (BMCs) are polyhedral structures that segregate enzymatic cargo from the cytosol via encapsulation within a protein shell. Unlike other biological polyhedra, such as viral capsids and encapsulins, BMC shells can exhibit a highly advantageous structural and functional plasticity, conforming to a variety of anabolic (CO 2 fixation in carboxysomes) and catabolic (nutrient assimilation in metabolosomes) roles. Consequently, understanding the subunit properties and associated protein–protein interaction processes that guide shell assembly and function is a necessary step to fully harness BMCs as modular, biotechnological nanomachines. Here, we describe the recent insights into the dynamics of structural features of the key BMC domain (Pfam00936)-containing proteins, which serve as a structural template for BMC-H and BMC-T shell building blocks.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Crystal Structure of VapBC-1 from Nontypeable Haemophilus influenzae and the Effect of PIN Domain Mutations on Survival during Infection

Toxin-antitoxin (TA) gene pairs have been identified in nearly all bacterial genomes sequenced to date and are thought to facilitate persistence and antibiotic tolerance. TA loci are classified into various types based upon the characteristics of their antitoxins, with those in type II expressing proteic antitoxins. Many toxins from type II modules are ribonucleases that maintain a PilT N-terminal (PIN) domain containing conserved amino acids considered essential for activity. The vapBC ( v irulence- a ssociated p rotein) TA system is the largest subfamily in this class and has been linked to pathogenesis of nontypeable Haemophilus influenzae (NTHi). In this study reported here, the crystal structure of the VapBC-1 complex from NTHi was determined to 2.20 Å resolution. Based on this structure, aspartate-to-asparagine and glutamate-to-glutamine mutations of four conserved residues in the PIN domain of the VapC-1 toxin were constructed and the effects of the mutations on protein-protein interactions, growth of Escherichia coli , and pathogenesis ex vivo were tested. Finally, a novel model system was designed and utilized that consists of an NTHi Δ vapBC-1 strain complemented in cis with the TA module containing a mutated or wild-type toxin at an ectopic site on the chromosome. This enabled the analysis of the effect of PIN domain toxin mutants in tandem with their wild-type antitoxin under the control of the vapBC-1 native promoter and in single copy. This is the first report of a system facilitating the study of TA mutant operons in the background of NTHi during infections of primary human tissues ex vivo .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Development of a concurrent coupled Atomistic - Continuum model to predict the defect and grain structure for Additive Manufacturing process [Slides]

Development of a coupled atomistic-continuum model for metal AM process. Two-way coupling between atomistic (heat flux) and continuum (temperature) domain. Identification of grain and dislocation structure at the atomistic domain. Conversion of dislocation data from discrete atomistic to density form at the continuum. Obtain the spatial distribution of grain structure and dislocation density in additively manufactured metal polycrystal material.

36 MATERIALS SCIENCE↗
DOE OSTI2018

Probing Dominant Negative Behavior of Glucocorticoid Receptor β through a Hybrid Structural and Biochemical Approach

Glucocorticoid receptor β (GR β ) is associated with glucocorticoid resistance via dominant negative regulation of GR α . To better understand how GR β functions as a dominant negative inhibitor of GR α at a molecular level, we determined the crystal structure of the ligand binding domain of GR β complexed with the antagonist RU-486. The structure reveals that GRβ binds RU-486 in the same ligand binding pocket as GR α , and furthermore, the unique C-terminal amino acids of GR β are mostly disordered. Binding energy analysis suggests that these C-terminal residues of GRβ do not contribute to RU-486 binding. Intriguingly, the GR β /RU-486 complex binds corepressor peptide with affinity similar to that of a GR α /RU-486 complex, despite the lack of helix 12. Our biophysical and biochemical analyses reveal that in the presence of RU-486, GR β is found in a conformation that favors corepressor binding, potentially antagonizing GR α function. This study thus presents an unexpected molecular mechanism by which GR β could repress transcription.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1990

Experiments in identification and control of flexible-link manipulators

A report is presented on an ongoing effort for end-point position control of flexible-link manipulators under realistic conditions in laboratory setups consisting of one- and two-link manipulators. The authors treat modeling, identification, and control of flexible-link manipulators that are required to carry payloads, possibly unknown and varying, while undergoing disturbance effects from the environments and the workspace. The various identification and control techniques being investigated are summarized, with emphasis on the ability of the controller to adjust to changes in dynamics, payload, and working environment. It is found that time-domain methods offer identified model structures that are readily available for control design, whereas frequency-domain methods, particularly the time-varying transfer function estimation approach developed for this application, are more desirable when rapid controller tuning is required.

Yurkovich, Stephen↗
DOE OSTI2014

Perfect coupling of light to a periodic dielectric/metal/dielectric structure

Using the finite difference time domain method, it is demonstrated that perfect coupling can be achieved between normally incident light and a periodic dielectric/metal/dielectric structure. The structure serves as a diffraction grating that excites modes related to the long range surface plasmon and short range surface plasmon modes that propagate on continuous metallic films. By optimizing the structural dimensions, perfect coupling is achieved between the incident light and these modes. A high Q of 697 and an accompanying ultrasharp linewidth of 0.8 nm are predicted for a 10 nm silver film for optimal conditions.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗
DOE OSTI2019

Differences in the path to exit the ribosome across the three domains of life

The ribosome exit tunnel is an important structure involved in the regulation of translation and other essential functions such as protein folding. By comparing 20 recently obtained cryo-EM and X-ray crystallography structures of the ribosome from all three domains of life, we here characterize the key similarities and differences of the tunnel across species. We first show that a hierarchical clustering of tunnel shapes closely reflects the species phylogeny. Then, by analyzing the ribosomal RNAs and proteins, we explain the observed geometric variations and show direct association between the conservations of the geometry, structure and sequence. We find that the tunnel is more conserved in the upper part close to the polypeptide transferase center, while in the lower part, it is substantially narrower in eukaryotes than in bacteria. Furthermore, we provide evidence for the existence of a second constriction site in eukaryotic exit tunnels. Overall, these results have several evolutionary and functional implications, which explain certain differences between eukaryotes and prokaryotes in their translation mechanisms. In particular, they suggest that major co-translational functions of bacterial tunnels were externalized in eukaryotes, while reducing the tunnel size provided some other advantages, such as facilitating the nascent chain elongation and enabling antibiotic resistance.

Biochemistry & Molecular Biology↗
DOE OSTI2018

Models for randomly distributed nanoscopic domains on spherical vesicles

The existence of lipid domains in the plasma membrane of biological systems has proven controversial, primarily due to their nanoscopic size—a length scale difficult to interrogate with most commonly used experimental techniques. Scattering techniques have recently proven capable of studying nanoscopic lipid domains populating spherical vesicles. However, the development of analytical methods able of predicting and analyzing domain pair correlations from such experiments has not kept pace. In our work, we developed models for the random distribution of monodisperse, circular nanoscopic domains averaged on the surface of a spherical vesicle. Specifically, the models take into account (i) intradomain correlations corresponding to form factors and interdomain correlations corresponding to pair distribution functions, and (ii) the analytical computation of interdomain correlations for cases of two and three domains on a spherical vesicle. In the case of more than three domains, these correlations are treated either by Monte Carlo simulations or by spherical analogs of the Ornstein-Zernike and Percus-Yevick (PY) equations. Importantly, the spherical analog of the PY equation works best in the case of nanoscopic size domains, a length scale that is mostly inaccessible by experimental approaches such as, for example, fluorescent techniques and optical microscopies. The analytical form factors and structure factors of nanoscopic domains populating a spherical vesicle provide a new and important framework for the quantitative analysis of experimental data from commonly studied phase-separated vesicles used in a wide range of biophysical studies.

73 NUCLEAR PHYSICS AND RADIATION PHYSICS↗
DOE OSTI2017

Molecular mechanics of Staphylococcus aureus adhesin, CNA, and the inhibition of bacterial adhesion by stretching collagen

Bacterial adhesion to collagen, the most abundant protein in humans, is a critical step in the initiation and persistence of numerous bacterial infections. In this study, we explore the collagen binding mechanism of the multi-modular cell wall anchored collagen adhesin (CNA) in Staphylococcus aureus and examine how applied mechanical forces can modulate adhesion ability. The common structural-functional elements and domain organization of CNA are present across over 50 genera of bacteria. Through the use of molecular dynamics models and normal mode analysis, we shed light on the CNA’s structural and conformational dynamics and its interactions with collagen that lead to collagen binding. Our results suggest that the linker region, CNA 165-173 , acts as a hinge exhibiting bending, extensional, and torsional modes of structural flexibility and its residues are key in the interaction of the CNA-collagen complex. Steered molecular dynamics simulations were conducted with umbrella sampling. During the course of these simulations, the ‘locking’ latch from the CNA N2 domain was dissociated from its groove in the CNA N1 domain, implying the importance of the latch for effective ligand binding. Finally, we observed that the binding efficiency of the CNA N1-N2 domains to collagen decreases greatly with increasing tensile force application to the collagen peptides. Thus, CNA and similar adhesins might preferentially bind to sites in which collagen fibers are cleaved, such as in wounded, injured, or inflamed tissues, or in which the collagenous tissue is less mature. As alternative techniques for control of bacterial infection are in-demand due to the rise of bacterial antibiotic resistance, results from our computational studies with respect to the mechanoregulation of the collagen binding site may inspire new therapeutics and engineering solutions by mechanically preventing colonization and/or further pathogenesis.

Science & Technology - Other Topics↗
DOE OSTI2017

Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5

The rapid spread of the recent Zika virus (ZIKV) epidemic across various countries in the American continent poses a major health hazard for the unborn fetuses of pregnant women. To date, there is no effective medical intervention. The nonstructural protein 5 of Zika virus (ZIKV-NS5) is critical for ZIKV replication through the 5'-RNA capping and RNA polymerase activities present in its N-terminal methyltransferase (MTase) and C-terminal RNA-dependent RNA polymerase (RdRp) domains, respectively. The crystal structure of the full-length ZIKV-NS5 protein has been determined at 3.05 Å resolution from a crystal belonging to space group P 2 1 2 1 2 and containing two protein molecules in the asymmetric unit. The structure is similar to that reported for the NS5 protein from Japanese encephalitis virus and suggests opportunities for structure-based drug design targeting either its MTase or RdRp domain.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Structures of a Nonribosomal Peptide Synthetase Module Bound to MbtH-like Proteins Support a Highly Dynamic Domain Architecture

Nonribosomal peptide synthetases (NRPSs) produce a wide variety of peptide natural products. During synthesis, the multidomain NRPSs act as an assembly line, passing the growing product from one module to the next. Each module generally consists of an integrated peptidyl carrier protein, an amino acid-loading adenylation domain, and a condensation domain that catalyzes peptide bond formation. Some adenylation domains interact with small partner proteins called MbtH-like proteins (MLPs) that enhance solubility or activity. A structure of an MLP bound to an adenylation domain has been previously reported using a truncated adenylation domain, precluding any insight that might be derived from understanding the influence of the MLP on the intact adenylation domain or on the dynamics of the entire NRPS module. Here, we present the structures of the full-length NRPS EntF bound to the MLPs from Escherichia coli and Pseudomonas aeruginosa. These new structures, along with biochemical and bioinformatics support, further elaborate the residues that define the MLP-adenylation domain interface. Additionally, the structures highlight the dynamic behavior of NRPS modules, including the module core formed by the adenylation and condensation domains as well as the orientation of the mobile thioesterase domain.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

Discovery and Structure-Based Optimization of Potent and Selective WD Repeat Domain 5 (WDR5) Inhibitors Containing a Dihydroisoquinolinone Bicyclic Core

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple chromatin-centric processes. Overexpression of WDR5 correlates with a poor clinical outcome in many human cancers, and WDR5 itself has emerged as an attractive target for therapy. Most drug-discovery efforts center on the WIN site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. In this paper, we describe discovery of a novel WDR5 WIN site antagonists containing a dihydroisoquinolinone bicyclic core using a structure-based design. These compounds exhibit picomolar binding affinity and selective concentration-dependent antiproliferative activities in sensitive MLL-fusion cell lines. Furthermore, these WDR5 WIN site binders inhibit proliferation in MYC-driven cancer cells and reduce MYC recruitment to chromatin at MYC/WDR5 co-bound genes. Thus, these molecules are useful probes to study the implication of WDR5 inhibition in cancers and serve as a potential starting point toward the discovery of anti-WDR5 therapeutics.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2023

MFA-DVR: direct volume rendering of MFA models

3D volume rendering is widely used to reveal insightful intrinsic patterns of volumetric datasets across many domains. However, the complex structures and varying scales of volumetric data can make efficiently generating high-quality volume rendering results a challenging task. Multivariate functional approximation (MFA) is a new data model that addresses some of the critical challenges: high-order evaluation of both value and derivative anywhere in the spatial domain, compact representation for large-scale volumetric data, and uniform representation of both structured and unstructured data. Here, in this paper, we present MFA-DVR, the first direct volume rendering pipeline utilizing the MFA model, for both structured and unstructured volumetric datasets. We demonstrate improved rendering quality using MFA-DVR on both synthetic and real datasets through a comparative study. We show that MFA-DVR not only generates more faithful volume rendering than using local filters but also performs faster on high-order interpolations on structured and unstructured datasets. MFA-DVR is implemented in the existing volume rendering pipeline of the Visualization Toolkit (VTK) to be accessible by the scientific visualization community.

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2016

Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation

The R-diastereomer of phosphorothioate analogs of cGMP, Rp-cGMPS, is one of few known inhibitors of cGMP-dependent protein kinase I (PKG I); however, its mechanism of inhibition is currently not fully understood. We determined the crystal structure of the PKG Iβ cyclic nucleotide-binding domain (PKG Iβ CNB-B), considered a ‘gatekeeper’ for cGMP activation, bound to Rp-cGMPS at 1.3 Å. Our structural and NMR data show that PKG Iβ CNB-B bound to Rp-cGMPS displays an apo-like structure with its helical domain in an open conformation. Comparison with the cAMP-dependent protein kinase regulatory subunit (PKA RIα) showed that this conformation resembles the catalytic subunit-bound inhibited state of PKA RIα more closely than the apo or Rp-cAMPS-bound conformations. Our results suggest that Rp-cGMPS inhibits PKG I by stabilizing the inactive conformation of CNB-B.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1988

Data dependent systems methodology for lumped mass modeling of structures

Limitations of the frequency domain methods in analyzing structura1 vibrations has created an awareness of the comparative merits of the time domain methods. Although time domain methods would be ideal for modeling large precisions space systems, the popular methods based on fitting theoretical response to actual data by least squares are too sensitive to noise and require too much data to be suitable for orbiting space crafts. This paper briefly reviews the theory and illustrative applications of a time domain methodology called Data Dependent Systems (DDS) that eliminates these limitations. Simulation results are presented to demonstrate a better than 4-place accuracy in the identifications of all system parameters, both modal (frequencies, damping ratios, and mode shapes) and physical (mass, stiffness, and damping matrices).

Pandit, Sudhakar M.↗
DOE OSTI2014

Hot-stage transmission electron microscopy study of (Na, K)NbO{sub 3} based lead-free piezoceramics

Hierarchical nanodomains assembled into micron-sized stripe domains, which is believed to be associated with outstanding piezoelectric properties, were observed at room temperature in a typical lead free piezoceramics, (Na{sub 0.52}K{sub 0.48−x})(Nb{sub 0.95−x}Ta{sub 0.05})-xLiSbO{sub 3}, with finely tuned polymorphic phase boundaries (x = 0.0465) by transmission electron microscopy. The evolution of domain morphology and crystal structure under heating and cooling cycles in the ceramic was investigated by in-situ hot stage study. It is found that the nanodomains are irreversibly transformed into micron-sized rectangular domains during heating and cooling cycles, which lead to the thermal instability of piezoelectric properties of the materials.

75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND↗