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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 865 records · Page 48
All sourcesNASA NTRSDOE OSTI
DOE OSTI2023

Structural basis of sequence-specific cytosine deamination by double-stranded DNA deaminase toxin DddA

The interbacterial deaminase toxin DddA catalyzes cytosine-to-uracil conversion in double-stranded (ds) DNA and enables CRISPR-free mitochondrial base editing, but the molecular mechanisms underlying its unique substrate selectivity have remained elusive. Here, we report crystal structures of DddA bound to a dsDNA substrate containing the 5'-TC target motif. These structures show that DddA binds to the minor groove of a sharply bent dsDNA and engages the target cytosine extruded from the double helix. DddA Phe1375 intercalates in dsDNA and displaces the 5' (-1) thymine, which in turn replaces the target (0) cytosine and forms a noncanonical T–G base pair with the juxtaposed guanine. This tandem displacement mechanism allows DddA to locate a target cytosine without flipping it into the active site. Biochemical experiments demonstrate that DNA base mismatches enhance the DddA deaminase activity and relax its sequence selectivity. On the basis of the structural information, we further identified DddA mutants that exhibit attenuated activity or altered substrate preference. Our studies may help design new tools useful in genome editing or other applications.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2020

Quantile-specific heritability of sibling leptin concentrations and its implications for gene-environment interactions

“Quantile-dependent expressivity” occurs when the effect size of a genetic variant depends upon whether the phenotype (e.g., leptin) is high or low relative to its distribution. Leptin concentrations are strongly related to adiposity, whose heritability is quantile dependent. Whether inheritance of leptin concentrations is quantile dependent, and whether this explains the greater heritability in women than men in accordance with their greater adiposity, and explains other gene-environment interactions, remains to be determined. Therefore, leptin and leptin receptor concentrations from 3068 siblings in 1133 sibships from the Framingham Heart Study Third Generation Cohort were analyzed. Free leptin index (FLI) was calculated as the ratio of leptin to soluble leptin receptor concentrations. Full-sib (β FS ) regression slopes were robustly estimated by quantile regression with nonparametric significance assigned from 1000 bootstrap samples. The analyses showed β FS increased significantly with increasing percentiles of the offspring’s age- and sex-adjusted leptin distribution (P linear = 0.0001), which was accelerated at the higher concentrations (P quadratic = 0.0003). β FS at the 90th percentile (0.418 ± 0.066) was 4.7-fold greater than at the 10th percentile (0.089 ± 0.032, P difference = 3.6 × 10 –6 ). Consistent with quantile-dependent expressivity, the β FS was greater in female sibs, which was attributable to their higher leptin concentrations. Reported gene-environment interactions involving adiposity and LEP , LEPR , MnSOD , PPARγ , PPARγ2 , and IRS-1 polymorphisms were consistent with quantile-dependent expressivity of leptin concentrations. β FS for leptin receptor concentrations and free leptin index also increased significantly with increasing percentiles of their distributions (P linear = 0.04 and P linear = 8.5 × 10 –6 , respectively). In conclusion, inherited genetic and shared environmental effects on leptin concentrations were quantile dependent, which likely explains male–female differences in heritability and some gene-environment interactions.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2023

Deep learning workflow for the inverse design of molecules with specific optoelectronic properties

The inverse design of novel molecules with a desirable optoelectronic property requires consideration of the vast chemical spaces associated with varying chemical composition and molecular size. First principles-based property predictions have become increasingly helpful for assisting the selection of promising candidate chemical species for subsequent experimental validation. However, a brute-force computational screening of the entire chemical space is decidedly impossible. To alleviate the computational burden and accelerate rational molecular design, we here present an iterative deep learning workflow that combines (i) the density-functional tight-binding method for dynamic generation of property training data, (ii) a graph convolutional neural network surrogate model for rapid and reliable predictions of chemical and physical properties, and (iii) a masked language model. As proof of principle, we employ our workflow in the iterative generation of novel molecules with a target energy gap between the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO).

97 MATHEMATICS AND COMPUTING↗
DOE OSTI2021

Huntingtin structure is orchestrated by HAP40 and shows a polyglutamine expansion-specific interaction with exon 1

Huntington’s disease results from expansion of a glutamine-coding CAG tract in the huntingtin (HTT) gene, producing an aberrantly functioning form of HTT. Both wildtype and disease-state HTT form a hetero-dimer with HAP40 of unknown functional relevance. Here, we demonstrate in vivo and in cell models that HTT and HAP40 cellular abundance are coupled. Integrating data from a 2.6 Å cryo-electron microscopy structure, cross-linking mass spectrometry, small-angle X-ray scattering, and modeling, we provide a near-atomic-level view of HTT, its molecular interaction surfaces and compacted domain architecture, orchestrated by HAP40. Native mass spectrometry reveals a remarkably stable hetero-dimer, potentially explaining the cellular inter-dependence of HTT and HAP40. The exon 1 region of HTT is dynamic but shows greater conformational variety in the polyglutamine expanded mutant than wildtype exon 1. Our data provide a foundation for future functional and drug discovery studies targeting Huntington’s disease and illuminate the structural consequences of HTT polyglutamine expansion.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2024

Ion-specific phenomena limit energy recovery in forward-biased bipolar membranes

The ability for bipolar membranes (BPMs) to interconvert voltage and pH makes them attractive materials for use in energy conversion and storage. Reverse-biased BPMs, which use electrical voltage to dissociate water into acid and base, have become increasingly well studied. However, forward-biased BPMs (FB-BPMs), in which voltage is extracted from pH gradients through recombination, require further study. Here physics-based modeling elucidates how the complex coupling of transport and kinetics dictates the performance of FB-BPMs in electrochemical devices. Simulations reveal that the open-circuit potential of FB-BPMs is dictated by the balance of ion recombination and crossover, where recombination of buffering counter-ions attenuates the open-circuit potential. Counter-ion mass-transport limitations and uptake of ionic impurities limit achievable current densities by reducing the applied pH gradient or the available fixed-charge sites that mediate recombination. Further, the model highlights the importance of selective ion management in mitigating energy losses and provides insight into the rational material design of FB-BPMs for energy applications.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗