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Siva K Angalakurthi, Connie A Tenorio, Michael Blaber, C Russell Middaugh
In this study, we examined the local dynamics of acidic fibroblast growth factor (FGF-1) as well as the binding sites of various polyanions including poly-sulfates (heparin and low MW heparin) and poly-phosphates (phytic acid and ATP) using hydrogen-deuterium exchange mass spectrometry (HX-MS). For local dynamics, results are analyzed at the peptide level as well as in terms of buried amides employing crystallographic B-factors and compared with a residue level heat map generated from HX-MS results. Results show that strand 4 and 5 and the turn between them to be the most flexible regions as was previously seen by NMR...
April 12, 2018: Protein Science: a Publication of the Protein Society
Futao Liu, Lin Zhu, Seok Rye Choi, Karl Plössl, Zhihao Zha, Hank F Kung
Positron emission tomography (PET) imaging of serotonin transporter (SERT) is useful for studying brain diseases with altered serotonergic function. A deuterated imaging agent, ([18 F]2-((2-((bis(methyl-d3)amino)methyl)-4-(3-fluoropropoxy- 1,1,2,2,3,3-d6)phenyl)thio)aniline, [18 F]D12FPBM, [18 F]1), was prepared as a new chemical entity (NCE). The deuterated agent, 1, showed excellent binding affinity to SERT; Ki was 0.086 nM, comparable to the un-deuterated FPBM. In vivo biodistribution studies in rats with [18 F]1 showed good brain uptake (1...
April 12, 2018: Journal of Labelled Compounds & Radiopharmaceuticals
Rachel C Klet, David M Kaphan, Cong Liu, Ce Yang, A Jeremy Kropf, Frédéric A Perras, Marek Pruski, Adam S Hock, Massimiliano Delferro
The chemical and electronic interactions of organometallic species with metal oxide support materials are of fundamental importance for the development of new classes of catalytic materials. Chemisorption of Cp*(PMe3 )IrMe2 on sulfated alumina (SA) and sulfated zirconia (SZ) led to an unexpected redox mechanism for deuteration of the ancillary Cp* ligand. Evidence for this oxidative mechanism was provided by studying the analogous homogeneous reactivity of the organometallic precursors toward trityl cation ([Ph3 C]+ ), a Lewis acid known to effect formal hydride abstraction by one-electron oxidation followed by hydrogen abstraction...
April 9, 2018: Journal of the American Chemical Society
Estella A Newcombe, Kiersten M Ruff, Ashish Sethi, Angelique R Ormsby, Yasmin M Ramdzan, Archa Fox, Anthony W Purcell, Paul R Gooley, Rohit V Pappu, Danny M Hatters
Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen-deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region...
April 5, 2018: Journal of Molecular Biology
Cesar A Ramirez-Sarmiento, Elizabeth A Komives
Hydrogen-deuterium exchange mass spectrometry (HDXMS) has emerged as a powerful approach for revealing folding and allostery in protein-protein interactions. The advent of higher resolution mass spectrometers combined with ion mobility separation and ultra-high liquid chromatographic separations have allowed the complete coverage of large protein sequences and multi-protein complexes. Liquid-handling robots have improved the reproducibility and accurate temperature control of the sample preparation. Many researchers are also appreciating the power of combining biophysical approaches such as stopped-flow fluorescence, single molecule FRET, and molecular dynamics simulations with HDXMS...
April 5, 2018: Methods: a Companion to Methods in Enzymology
L A Zepeda-Ruiz, B Sadigh, S J Shin, B J Kozioziemski, A A Chernov
We have performed a computational study to determine how the wetting of liquid deuterium to the walls of the material influences nucleation. We present the development of a pair-wise interatomic potential that includes zero-point motion of molecular deuterium. Deuterium is used in this study because of its importance to inertial confinement fusion and the potential to generate a superfluid state if the solidification can be suppressed. Our simulations show that wetting dominates undercooling compared to the pore geometries...
April 7, 2018: Journal of Chemical Physics
Thomas E Bohl, Pek Ieong, John K Lee, Thomas Lee, Jayakanth Kankanala, Ke Shi, Özlem Demir, Kayo Kurahashi, Rommie E Amaro, Zhengqiang Wang, Hideki Aihara
Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen-deuterium exchange mass spectrometry provided evidence for a highly flexible substrate-binding cap in LpxH...
April 6, 2018: Journal of Biological Chemistry
Dominic Narang, Wei Chen, Clarisse G Ricci, Elizabeth A Komives
The main NFκB transcription factor family members RelA-p50 heterodimer and RelA homodimer have different biological functions and show different transcriptional activation profiles. To investigate whether the two family members adopt a similar conformation in their free states, we performed hydrogen-deuterium exchange mass spectrometry (HDXMS), all-atom molecular dynamics (MD) simulations and stopped-flow binding kinetics experiments. Surprisingly, the N-terminal DNA binding domains adopt an open conformation in RelA-p50 but a closed conformation in RelA homodimer...
April 3, 2018: Journal of Molecular Biology
Christina Dal Magro, Patrick Keller, Annika Kotter, Stephan Werner, Victor Duarte, Virginie Marchand, Michael Ignarski, Anja Freiwald, Roman-Ulrich Müller, Christoph Dieterich, Yuri Motorin, Falk Butter, Mohammed Atta, Mark Helm
Recently discovered new chemical entities in RNA modifications have provided surprises with respect to functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over one hundred signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds, representing new structures of RNA modifications. One structure was elucidated by deuterium exchange and high resolution mass spectrometry...
April 6, 2018: Angewandte Chemie
Yifu Yu, Bin Zhang
A facile and efficient method for deuterium incorporation has been developed by merging photocatalytic C-X bond dissociation and water splitting with porous CdSe nanosheets as the photocatalyst under mild reaction conditions. This reaction displays good functional group tolerance and high selectivity with regard to the number and position of incorporated deuterium atoms, and can be used for the construction of complex molecules in tandem processes.
April 6, 2018: Angewandte Chemie
Aaron A Cook, Wei Deng, Jinqi Ren, Renhao Li, John Sondek, Wolfgang Bergmeier
Platelets are recruited to sites of vascular injury where they are activated and aggregate to form a hemostatic plug. This process requires the activation of the small GTPase Rap1B by its cognate guanine nucleotide exchange factor CalDAG-GEFI. Studies on platelet function suggest that CalDAG-GEFI activity is regulated by changes in cytosolic calcium, but the exact molecular mechanism is poorly understood. Here, we show that purified CalDAG-GEFI is autoinhibited and directly regulated by calcium. Substitutions of putative calcium-binding residues within the canonical EF hands of CalDAG-GEFI diminish its capacity to activate Rap1B...
April 5, 2018: Journal of Biological Chemistry
Stjepko Faziniċ, Tonči Tadić, Marin Vukšić, Marek Rubel, Per Petersson, Elżbieta Fortuna-Zaleśna, Anna Widdowson
Generation of metal dust in the JET tokamak with the ITER-like wall (ILW) is a topic of vital interest to next-step fusion devices because of safety issues with plasma operation. Simultaneous Nuclear Reaction Analysis (NRA) and Particle-Induced X-ray Emission (PIXE) with a focused 4 MeV3 He micro-beam was used to determine the composition of dust particles related to the JET operation with the ILW. The focus was on 'Be-rich particles' collected from the deposition zone on the inner divertor tile. The particles found are composed of a mix of co-deposited species up to 120 µm in size with a thickness of 30-40 µm...
April 5, 2018: Analytical Chemistry
Rui Wang, Mengyue Ma, Xu Gong, Grace B Panetti, Xinyuan Fan, Patrick J Walsh
A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D2 O as an inexpensive deuterium source (≥95% D ratio). The mechanism of this unusual transformation is probed.
April 5, 2018: Organic Letters
Danilo Donnarumma, Claudio Maestri, Pietro Ivan Giammarinaro, Luigi Capriotti, Erika Bartolini, Daniele Veggi, Roberto Petracca, Maria Scarselli, Nathalie Norais
Hydrogen Deuterium exchange (HDx) associated with Mass Spectrometry (MS) is emerging as a powerful tool to provide conformational information on membrane proteins. Unfortunately, as for X-ray diffraction and NMR, HDx performed on reconstituted in vitro systems might not always reflect the in vivo environment. Outer Membrane Vesicles naturally released by E. coli were used to carry out analysis of native OmpF through HDx-MS. A new protocol compatible with HDx analysis and avoiding hindrance from the lipid contents was set-up...
April 5, 2018: Journal of Proteome Research
Alberto M Lopez, Ahmad A Ibrahim, Gregory J Rosenhauer, Hansamali S Sirinimal, Jennifer L Stockdill
A tin-free strategy for the successful cyclization of a variety of internal alkyne-containing N-chloroamine precursors to the ABC core via cyclization of a neutral aminyl radical is established. Deuterium labeling experiments confirm that the solvent is the primary source of the final H atom in the cyclization cascade. These conditions enabled a streamlined route to a β-ketoester intermediate poised for intramolecular Knoevenagel condensation to construct the seven-membered D-ring of calyciphylline A alkaloids...
April 3, 2018: Organic Letters
Brent A Kochert, Roxana E Iacob, Thomas E Wales, Alexandros Makriyannis, John R Engen
Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) can provide valuable information about binding, allostery, and other conformational effects of interaction in protein complexes. For protein-ligand complexes, where the ligand may be a small molecule, peptide, nucleotide, or another protein(s), a typical experiment measures HDX in the protein alone and then compares that with HDX for the protein when part of the complex. Multiple factors are critical in the design and implementation of such experiments, including thoughtful consideration of the percent protein bound, the effects of the labeling protocol on the protein complex, and the dynamic range of the analysis method...
2018: Methods in Molecular Biology
Elżbieta Winnicka, Marianna Kańska
We report the enzymatic synthesis of the derivatives of L-tryptophan methylated in indole moiety and labeled with deuterium and tritium in the 2-position of side chain. For kinetic studies twelve isotopomers, i.e., 1'-methyl-[2-2 H]-, 1'-methyl-[2-3 H]-, 1'-methyl-[2-2 H/3 H]-, 2'-methyl-[2-2 H]-, 2'-methyl-[2-3 H]-, 2'-methyl-[2-2 H/3 H]-, 5'-methyl-[2-2 H]-, 5'-methyl-[2-3 H]-, 5'-methyl-[2-2 H/3 H]-, 7'-methyl-[2-2 H]-, 7'-methyl-[2-3 H]-, and 7'-methyl-[2-2 H/3 H]-L-tryptophan are obtained by the enzymatic coupling of the appropriate methylated indole moiety with S-methyl-L-cysteine catalyzed by the enzyme tryptophanase...
March 27, 2018: Applied Radiation and Isotopes
Nikolai F Bunkin, Valeriy A Kozlov, Alexey V Shkirin, Barry W Ninham, Anatoliy A Balashov, Sergey V Gudkov
Experiments with Fourier transform spectrometry of Nafion, a water-swollen polymeric membrane, are described. The transmittance spectra of liquid samples and Nafion, soaked in these samples, were studied, depending on the deuterium content in water in the spectral range 1.8-2.15 μm. The experiments were carried out using two protocols: in the first protocol we studied the dynamics of Nafion swelling in H2 O + D2 O mixtures for the deuterium concentrations 3 < C < 104 ppm, and in the second protocol we studied the dynamics of swelling in pure heavy water (C = 106 ppm)...
March 28, 2018: Journal of Chemical Physics
Stefan Döge, Jürgen Hingerl
The improvement of the number of extractable ultracold neutrons (UCNs) from converters based on solid deuterium (sD2 ) crystals requires a good understanding of the UCN transport and how the crystal's morphology influences its transparency to the UCNs. Measurements of the UCN transmission through cryogenic liquids and solids of interest, such as hydrogen (H2 ) and deuterium (D2 ), require sample containers with thin, highly polished and optically transparent windows and a well defined sample thickness. One of the most difficult sealing problems is that of light gases like hydrogen and helium at low temperatures against high vacuum...
March 2018: Review of Scientific Instruments
Yury Kostyukevich, Thamina Acter, Alexander Zherebker, Arif Ahmed, Sunghwan Kim, Eugene Nikolaev
The isotopic exchange approach is in use since the first observation of such reactions in 1933 by Lewis. This approach allows the investigation of the pathways of chemical and biochemical reactions, determination of structure, composition, and conformation of molecules. Mass spectrometry has now become one of the most important analytical tools for the monitoring of the isotopic exchange reactions. Investigation of conformational dynamics of proteins, quantitative measurements, obtaining chemical, and structural information about individual compounds of the complex natural mixtures are mainly based on the use of isotope exchange in combination with high resolution mass spectrometry...
March 30, 2018: Mass Spectrometry Reviews
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