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Results for “CP: Molecular biology”

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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11 records
All sourcesNASA NTRSDOE OSTI
DOE OSTI2024

Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes

Mutations that cause familial Alzheimer’s disease (FAD) are found in amyloid precursor protein (APP) and presenilin, the catalytic component of γ-secretase, that together produce amyloid β-peptide (Aβ). Nevertheless, whether Aβ is the primary disease driver remains controversial. We report here that FAD mutations disrupt initial proteolytic events in the multistep processing of APP substrate C99 by γ-secretase. Cryoelectron microscopy reveals that a substrate mimetic traps γ-secretase during the transition state, and this structure aligns with activated enzyme-substrate complex captured by molecular dynamics simulations. In silico simulations and in cellulo fluorescence microscopy support stabilization of enzyme-substrate complexes by FAD mutations. Neuronal expression of C99 and/or presenilin-1 in Caenorhabditis elegans leads to synaptic loss only with FAD-mutant transgenes. Designed mutations that stabilize the enzyme-substrate complex and block Aβ production likewise led to synaptic loss. Collectively, these findings implicate the stalled process—not the products—of γ-secretase cleavage of substrates in FAD pathogenesis.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

PigmentHunter: A point-and-click application for automated chlorophyll-protein simulations

Chlorophyll proteins (CPs) are the workhorses of biological photosynthesis, working together to absorb solar energy, transfer it to chemically active reaction centers, and control the charge-separation process that drives its storage as chemical energy. Yet predicting CP optical and electronic properties remains a serious challenge, driven by the computational difficulty of treating large, electronically coupled molecular pigments embedded in a dynamically structured protein environment. To address this challenge, we introduce here an analysis tool called PigmentHunter, which automates the process of preparing CP structures for molecular dynamics (MD), running short MD simulations on the nanoHUB.org science gateway, and then using electrostatic and steric analysis routines to predict optical absorption, fluorescence, and circular dichroism spectra within a Frenkel exciton model. Inter-pigment couplings are evaluated using point-dipole or transition-charge coupling models, while site energies can be estimated using both electrostatic and ring-deformation approaches. The package is built in a Jupyter Notebook environment, with a point-and-click interface that can be used either to manually prepare individual structures or to batch-process many structures at once. Here, we illustrate PigmentHunter’s capabilities with example simulations on spectral line shapes in the light harvesting 2 complex, site energies in the Fenna–Matthews–Olson protein, and ring deformation in photosystems I and II.

14 SOLAR ENERGY↗
DOE OSTI2024

High incidence and geographic distribution of cleft palate in Finland are associated with the IRF6 gene

In Finland, the frequency of isolated cleft palate (CP) is higher than that of isolated cleft lip with or without cleft palate (CL/P). This trend contrasts to that in other European countries but its genetic underpinnings are unknown. We conducted a genome-wide association study in the Finnish population and identified rs570516915, a single nucleotide polymorphism highly enriched in Finns, as strongly associated with CP (P = 5.25 × 10 -34 , OR = 8.65, 95% CI 6.11-12.25), but not with CL/P (P = 7.2 × 10 -5 ), with genome-wide significance. The risk allele frequency of rs570516915 parallels the regional variation of CP prevalence in Finland, and the association was replicated in independent cohorts of CP cases from Finland (P = 8.82 × 10 -28 ) and Estonia (P = 1.25 × 10 -5 ). The risk allele of rs570516915 alters a conserved binding site for the transcription factor IRF6 within an enhancer (MCS-9.7) upstream of the IRF6 gene and diminishes the enhancer activity. Oral epithelial cells derived from CRISPR-Cas9 edited induced pluripotent stem cells demonstrate that the CP-associated allele of rs570516915 concomitantly decreases the binding of IRF6 and the expression level of IRF6, suggesting impaired IRF6 autoregulation as a molecular mechanism underlying the risk for CP.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Bioinspired oxidation of benzyl alcohol: The role of environment and nuclearity of the catalyst evaluated by multivariate analysis

Inspired by copper-containing enzymes such as galactose oxidase and catechol oxidase, in which distinct coordination environments and nuclearities lead to specific catalytic activities, we summarize here the catalytic properties of dinuclear and mononuclear copper species towards benzyl alcohol oxidation using a multivariate statistical approach. Here, the new dinuclear [Cu 2 (μ-L 1 )(μ-pz)] 2+ (1) is compared against the mononuclear [CuL 2 Cl] (2), where (L 1 ) - and (L 2 ) - are the respective deprotonated forms of 2,6-bis((bis(pyridin-2-ylmethyl)amino)methyl)-4-methylphenol, and 3-((bis(pyridin-2-ylmethyl)amino)methyl)-2-hydroxy-5-methylbenzaldehyde and (pz) - is a pyrazolato bridge. Copper(II) perchlorate (CP) is used as control. The catalytic oxidation of benzyl alcohol is pursued, aiming to assess the role of the ligand environment and nuclearity. The multivariate statistical approach allows for the search of optimal catalytic conditions, considering variables such as catalyst load, hydrogen peroxide load, and time. Species 1, 2 and CP promoted selective production of benzaldehyde at different yields, with only negligible amounts of benzoic acid. Under normalized conditions, 2 showed superior catalytic activity. This species is 3.5-fold more active than the monometallic control CP, and points out to the need for an efficient ligand framework. Species 2 is 6-fold more active than the dinuclear 1, and indicates the favored nuclearity for the conversion of alcohols into aldehydes.

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

High Bio-Content Thermoplastic Polyurethanes from Azelaic Acid

To realize the commercialization of sustainable materials, new polymers must be generated and systematically evaluated for material characteristics and end-of-life treatment. Polyester polyols made from renewable monomers have found limited adoption in thermoplastic polyurethane (TPU) applications, and their broad adoption in manufacturing may be possible with a more detailed understanding of their structure and properties. To this end, we prepared a series of bio-based crystalline and amorphous polyester polyols utilizing azelaic acid and varying branched or non-branched diols. The prepared polyols showed viscosities in the range of 504–781 cP at 70 °C, with resulting TPUs that displayed excellent thermal and mechanical properties. TPUs prepared from crystalline azelate polyester polyol exhibited excellent mechanical properties compared to TPUs prepared from amorphous polyols. These were used to demonstrate prototype products, such as watch bands and cup-shaped forms. Importantly, the prepared TPUs had up to 85% bio-carbon content. Studies such as these will be important for the development of renewable materials that display mechanical properties suitable for commercially viable, sustainable products.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Novel viruses of the family Partitiviridae discovered in Saccharomyces cerevisiae

It has been 49 years since the last discovery of a new virus family in the model yeast Saccharomyces cerevisiae . A large-scale screen to determine the diversity of double-stranded RNA (dsRNA) viruses in S . cerevisiae has identified multiple novel viruses from the family Partitiviridae that have been previously shown to infect plants, fungi, protozoans, and insects. Most S . cerevisiae partitiviruses (ScPVs) are associated with strains of yeasts isolated from coffee and cacao beans. The presence of partitiviruses was confirmed by sequencing the viral dsRNAs and purifying and visualizing isometric, non-enveloped viral particles. ScPVs have a typical bipartite genome encoding an RNA-dependent RNA polymerase (RdRP) and a coat protein (CP). Phylogenetic analysis of ScPVs identified three species of ScPV, which are most closely related to viruses of the genus Cryspovirus from the mammalian pathogenic protozoan Cryptosporidium parvum . Molecular modeling of the ScPV RdRP revealed a conserved tertiary structure and catalytic site organization when compared to the RdRPs of the Picornaviridae . The ScPV CP is the smallest so far identified in the Partitiviridae and has structural homology with the CP of other partitiviruses but likely lacks a protrusion domain that is a conspicuous feature of other partitivirus particles. ScPVs were stably maintained during laboratory growth and were successfully transferred to haploid progeny after sporulation, which provides future opportunities to study partitivirus-host interactions using the powerful genetic tools available for the model organism S . cerevisiae .

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Thiourea-Derived Chelating Ligands and Their Organometallic Compounds: Investigations into Their Anticancer Activity

Thiones have been investigated as ligands in metal complexes with catalytic and biological activity. We report the synthesis, characterization, and biological evaluation of a series of MII/III complexes of the general formulae [M II (cym)(L)Cl]X (cym = η 6 -p-cymene) or [M III (Cp*)(L)Cl]X (Cp* = η 5 -pentamethylcyclopentadienyl), where X = Cl - or PF 6 - , and L represents heterocyclic derivatives of thiourea. The thiones feature a benzyl-triazolyl pendant and they act as bidentate ligands via N,S-coordination to the metal centers. Several derivatives have been investigated by single-crystal X-ray diffraction analysis. NMR investigations showed a counterion-dependent shift of several protons due to the interaction with the counterions. These NMR investigations were complemented with X-ray diffraction analysis data and the effects of different counterions on the secondary coordination sphere were also investigated by DFT calculations. In biological studies, the Ir benzimidazole derivative was found to accumulate in the cytoplasm and it was the most cytotoxic derivative investigated.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2024

Selective Detection of Intermediate-Amplitude Motion by Solid-State NMR

The coexistence of rigid and mobile molecules or molecular segments abounds in biomolecular assemblies. Examples include the carbohydrate-rich cell walls of plants and intrinsically disordered proteins that contain rigid β-sheet cores. In solid-state nuclear magnetic resonance (NMR) spectroscopy, dipolar polarization transfer experiments are well suited for detecting rigid components, whereas scalar-coupling experiments are well suited for detecting highly mobile components. However, few NMR methods are available to detect the segments that undergo intermediate-amplitude fast motion. Here, we introduce two NMR experiments, a two-dimensional T 2H -filtered CP-hCH correlation and a three-dimensional J-INADEQUATE CCH correlation, to observe this intermediate-amplitude motion. Both experiments involve 1 H detection under fast magic-angle spinning (MAS). By combining 1 H transverse relaxation (T 2H ) filters with dipolar polarization transfer, we suppress the signals of both highly rigid and highly mobile species, thus revealing the signals of intermediate mobile species. 1 H detection under fast MAS is crucial for distinguishing the different motional amplitudes. Here, we demonstrate these techniques on several plant cell wall samples and show that they allow the selective detection and resolution of certain hemicellulose and pectin signals, which are usually masked by the signals of the rigid cellulose and the highly dynamic pectins in purely dipolar and scalar NMR spectra.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Evidence of Atypical Structural Flexibility of the Active Site Surrounding of an [FeFe] Hydrogenase from Clostridium beijerinkii

[FeFe] hydrogenase from Clostridium beijerinkii (CbHydA1) is an unusual hydrogenase in that it can withstand prolonged exposure to O 2 by reversibly converting into an O 2 -protected, inactive state (Hinact). It has been indicated in the past that an atypical conformation of the “SC 367 CP” loop near the [2Fe] H portion of the six-iron active site (H-cluster) allows the Cys367 residue to adopt an “off-H + -pathway” orientation, promoting a facile transition of the cofactor to Hinact. Here, we investigated the electronic structure of the H-cluster in the oxidized state (H ox ) that directly converts to Hinact under oxidizing conditions and the related CO-inhibited state (H ox -CO). We demonstrate that both states exhibit two distinct forms in electron paramagnetic resonance (EPR) spectroscopy. The ratio between the two forms is pH-dependent but also sensitive to the buffer choice. Our IR and EPR analyses illustrate that the spectral heterogeneity is due to a perturbation of the coordination environment of the H-cluster’s [4Fe4S] H subcluster without affecting the [2Fe] H subcluster. Overall, we conclude that the observation of two spectral components per state is evidence of heterogeneity of the environment of the H-cluster likely associated with conformational mobility of the SCCP loop. Such flexibility may allow Cys367 to switch rapidly between off- and on-H + -pathway rotamers. Consequently, we believe such structural mobility may be the key to maintaining high enzymatic activity while allowing a facile transition to the O 2 -protected state.

08 HYDROGEN↗
DOE OSTI2026

Exploration of Nirmatrelvir Derivatives as Optimized SARS‐CoV‐2 Antivirals

Nirmatrelvir (NMV) is a SARS‐CoV‐2 antiviral component of the approved COVID‐19 therapeutic Paxlovid. It is a reversible covalent inhibitor of SARS‐CoV‐2 main protease (M Pro ) that is effluxed from human cells by P‐glycoprotein (P‐gp). To identify NMV analogs with improved potency and reduced P‐gp efflux, a structure–activity relationship campaign was conducted. Warheads alternative to nitrile for engaging the active site cysteine were tested showing aldehyde and dichloroacetamide with better enzyme inhibition potency. Crystal structure of MPI‐136−M Pro shows its aldehyde warhead forming a thiohemiacetal with active Cys145 of M Pro . Several S4 binders were explored revealing that an O‐to‐S shift at the N ‐terminal amide leads to better enzyme inhibition. By exploring different combinations of S2, S3, and S4 binders, two inhibitors with better enzyme inhibition potency than NMV were found. Crystal structure of MPI‐148, with ( S )‐2‐azaspiro[4,5]decane‐3‐carboxylate as an alternative S2 binder, shows extensive hydrogen‐bond networks for locking the inhibitor in active site, explaining high affinity of NMV analogs. Further characterization of cellular M Pro engagement and antiviral potency against SARS‐CoV‐2 revealed four inhibitors with greater potency than NMV in P‐gp‐expressing cells. Studies with the P‐gp inhibitor CP‐100356 showed that these compounds were less sensitive to P‐gp inhibition than NMV, consistent with reduced P‐gp‐mediated efflux.

Alugubelli, Yugendar R. [Texas A&M Drug Discovery ↗
DOE OSTI2025

GLBRC Soil Yearlong Incubation 13C-SIP-Lipidomics

Data package for Lipids represent a dynamic, yet stable pool of microbially-derived soil carbon This data is published under a CC0 license. The authors encourage data reuse and request attribution by referencing the below citations for the data packages and associated manuscript. Please cite as: Rempfert KR, Bell SL, Kasanke CP, Kyle JE, Hofmockel KS. 2025. GLBRC Soil Yearlong Incubation 13C-SIP-Lipidomics. [Data Set] PNNL DataHub. doi: Rempfert KR, Bell SL, Kasanke CP, Kyle JE, Hofmockel KS. 2025. MSV000097435: GLBRC soil yearlong incubation 13C-SIP-Lipidomics [Data Set] MassIVE. doi:10.25345/C57659T3K Rempfert KR, Bell SL, Kasanke CP, Kyle JE, Hofmockel KS. 2025. Lipids represent a dynamic, yet stable pool of microbially-derived soil carbon. In Prep This data package consists of compound-specific 13C SIP-lipidomics data from a yearlong tracer incubation experiment designed to investigate microbial lipid persistence in switchgrass bioenergy crop soils. In order to explore how lipid structure may modulate the persistence of C in soil lipids, we leveraged soils from two sites (Michigan - sandy texture, Wisconsin - silty texture) operated by the U.S. Department of Energy-funded Great Lakes Bioenergy Research Center (GLBRC). These sites had comparable climates, identical management practices, but contrasting soil textures, allowing us to assess the variability of lipid accrual or degradation in soils as well as provide insight regarding the degree to which edaphic properties may regulate the retention of soil lipids. Untargeted lipidomics analyses were performed to identify 13C-labeled lipids in the soil microbiome after long-term incubation. Soils were supplemented with 100 micrograms glucose per gram dry soil (99 atom % 13C or natural abundance for paired control) and incubated; samples were collected two months and one year after glucose addition. Lipid extracts (MPLEx) were analyzed by LC-MS/MS and identified using LIQUID. Calculation of isotopic enrichment of lipids was performed by targeted approach using TarMet to quantify lipid isotopologues and IsoCorrectoR to correct for natural abundance isotopes. Contents: Data package contents reported here are the first version and contain downstream analysis files for the raw LC-MS mass spectrometry files (.mzXML) deposited at the MassIVE database repository under accession MSV000097435 (80 experimental runs; 5.85 GB) | MassIVE DOI: 10.25345/C57659T3K. Support files include the additional data download 'Read Me' file containing data descriptor information. Reported data download contents are structured for compliance with project data sharing guidelines, community standards initiatives, and sponsor stakeholder policies supporting FAIR data principles. Data processing software, analysis tools, and data workflows are listed below corresponding to the host repository long-term location. Available Data Downloads (0.3 GB): "GLBRC soil yearlong incubation 13C-SIP-Lipidomics_readme.txt" - 'Read Me' data package content file (txt) "GLBRC_DataPackage_analysis files" - Data processing files (Rmd) and saved intermediate data processing outputs (rds, csv, xlsx) "GLBRC_13C_lipidomics_dataset.xlsx" - processed data in tabular format (xlsx) Linked Software: LIQUID LC-MS Analysis Software | 10.5281/zenodo.6459462 Lipid Mini-On Software Tools | 10.5281/zenodo.1492803 pmartR Omics Statistical Software | 10.5281/zenodo.6108667 xcms (v4.3.3) TarMet (v1.1.1) IsoCorrectoR (1.24.0) Funding Acknowledgments: This research was supported by an Early Career Research Program award funded by the U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research (OBER) Genomic Science program under FWP 68292, FWP 07880 and EMSL Exploratory Research Project 51095. A portion of this work was performed in the William R. Wiley Environmental Molecular Sciences Laboratory, a national scientific user facility sponsored by OBER and located at Pacific Northwest National Laboratory (PNNL). PNNL is a multi-program national laboratory operated by Battelle for the DOE under Contract DE-AC05-76RLO1830.

Rempfert, Kaitlin R [Pacific Northwest National La↗