Chemistry & Biochemistry
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- Item1,3-Diphenylisobenzofuran(International Union of Crystallography, 2008) Boeré, René T.; Dibble, Peter W.; Fischer, Kristapher E.
- Item1,5-(4,4'-Dipyridyl)naphthalene(MDPI, 2015) Hassan, Mohammad R.; Boeré, René T.The title compound has been prepared from 1,5-dibromonaphthalene (obtained from 1,5-diaminonaphthalene) using Suzuki-Miyaura cross-coupling to 4-pyridylboronic acid. The crystal and molecular structure was determined by single-crystal X-ray diffraction.
- Item1-methyl-4-thiocarbamoylpyridin-1-ium iodide(International Union of Crystallography, 2018) Shotonwa, Ibukun O.; Boeré, René T.In the title compound, C7H9N2S+·I−, the thioamide moiety is twisted out of the aromatic plane by 38.98 (4)° and forms N—H...I hydrogen bonds. In the crystal, hydrogen-bonded centrosymmetric dimers [C7H9N2S+·I−]2 are linked via additional short contacts from an aromatic CH group to the iodide anion into ribbons parallel to the (010) plane.
- Item2'-acetonaphthone(International Union of Crystallography, 2012) Shotonwa, Ibukun O.; Boeré, René T.
- Item2D analysis of polydisperse core-shell nanoparticles using analytical ultracentrifugation(Royal Society of Chemistry, 2017) Walter, Johannes; Gorbet, Gary E.; Akdas, Tugce; Segets, Doris; Demeler, Borries; Peukert, WolfgangAccurate knowledge of the size, density and composition of nanoparticles (NPs) is of major importance for their applications. In this work the hydrodynamic characterization of polydisperse core–shell NPs by means of analytical ultracentrifugation (AUC) is addressed. AUC is one of the most accurate techniques for the characterization of NPs in the liquid phase because it can resolve particle size distributions (PSDs) with unrivaled resolution and detail. Small NPs have to be considered as core–shell systems when dispersed in a liquid since a solvation layer and a stabilizer shell will significantly contribute to the particle's hydrodynamic diameter and effective density. AUC measures the sedimentation and diffusion transport of the analytes, which are affected by the core–shell compositional properties. This work demonstrates that polydisperse and thus widely distributed NPs pose significant challenges for current state-of-the-art data evaluation methods. The existing methods either have insufficient resolution or do not correctly reproduce the core–shell properties. First, we investigate the performance of different data evaluation models by means of simulated data. Then, we propose a new methodology to address the core–shell properties of NPs. This method is based on the parametrically constrained spectrum analysis and offers complete access to the size and effective density of polydisperse NPs. Our study is complemented using experimental data derived for ZnO and CuInS2 NPs, which do not have a monodisperse PSD. For the first time, the size and effective density of such structures could be resolved with high resolution by means of a two-dimensional AUC analysis approach.
- Item(2R,3aR,4S,7R,7aS,9R,10aR,11S,14R,14aS)-rel-3a,4,7,7a,10a,11,14,14aOctahydro-4,14:7,11-diepoxy-2,9propanonaphtho[1,2-f:5,6-f000]diisoindole1,3,8,10-tetrone (9CI): a cyclophane derived from naphtho[1,2-c:5,6-c]difuran(International Union of Crystallography, 2008) Thibault, Michelle E.; Parvez, Masood; Dibble, Peter W.The title compound, C25H18N2O6, is a naphthalenophane styled in the manner of Warrener's alicyclic cyclophanes or molecular racks wherein a trimethylene tether is perfectly staggered between the two N atoms such that the central methylene H atoms point toward the naphthalene [pi]-system. The dihedral angle between the mean planes of the two benzene rings is 7.61 (7)°.
- Item3,5-diphenyl-1,2,4-dithiazolium tetrabromidoferrate(III)(International Union of Crystallography, 2013) Shotonwa, Ibukun O.; Boeré, René T.
- Item3,7-Di-tert-butyl-1,5,2,4,6,8-dithiatetrazocine(International Union of Crystallography, 1995) Parvez, Masood; Boeré, René T.; Derrick, Sean; Moock, Klaus H.The eight-membered ring in the title compound, C10HI8N4S2, lies about an inversion centre and is essentially planar with normal bond lengths and angles [mean C--S 1.569 (2) and mean C--N 1.326 (3)A].
- Item4-hydrazinopyridinium chloride(International Union of Crystallography, 2009) Boeré, René T.; Hassan, Mohammad R.
- Item4-methyl-N'-(2,2,2-trichloroethanimidoyl)benzene-1-carboximidamide(International Union of Crystallography, 2011) Roemmele, Tracey L.; Boeré, René T.
- Item4-thiocarbamoylpyridin-1-ium iodide(International Union of Crystallography, 2014) Shotonwa, Ibukun O.; Boeré, René T.
- Item4S-fluorination of ProB29 in insulin lispro slows fibril formation(Elsevier, 2024) Breunig, Stephanie L.; Chapman, Alex M.; LeBron, Jeanne; Quijano, Janine C.; Ranasinghe, Maduni; Rawson, Jeffrey; Demeler, Borries; Ku, Hsun Teresa; Tirrell, David A.Recombinant insulin is a life-saving therapeutic for millions of patients affected by diabetes mellitus. Standard mutagenesis has led to insulin variants with improved control of blood glucose; for instance, the fast-acting insulin lispro contains two point mutations that suppress dimer formation and expedite absorption. However, insulins undergo irreversible denaturation, a process accelerated for the insulin monomer. Here we replace ProB29 of insulin lispro with 4R-fluoroproline, 4S-fluoroproline, and 4,4-difluoroproline. All three fluorinated lispro variants reduce blood glucose in diabetic mice, exhibit similar secondary structure as measured by CD, and rapidly dissociate from the zinc- and resorcinol-bound hexamer upon dilution. Notably, however, we find that 4S-fluorination of ProB29 delays the formation of undesired insulin fibrils that can accumulate at the injection site in vivo and can complicate insulin production and storage. These results demonstrate how subtle molecular changes achieved through non-canonical amino acid mutagenesis can improve the stability of protein therapeutics.
- Item(5Z,7Z,9Z)-5,10-dibromobenzo[8]-annulene(International Union of Crystallography, 2013) Bender, Christopher O.; Boeré, René T.
- ItemA new UltraScan module for the characterization and quantification of analytical buoyant density equilibrium experiments to determine AAV capsid loading(Springer, 2023) Savelyev, Alexey; Brookes, Emre H.; Henrickson, Amy; Demeler, BorriesA method for characterizing and quantifying peaks formed in an analytical buoyant density equilibrium (ABDE) experiment is presented. An algorithm is derived to calculate the concentration of the density forming gradient material at every point in the cell, provided the rotor speed, temperature, meniscus position, bottom of the cell position, and the loading concentration, molar mass, and partial specific volume of the density gradient-forming material are known. In addition, a new peak fitting algorithm has been developed which allows the user to automatically quantify the peaks formed in terms of density, apparent partial specific volume, and relative abundance. The method is suitable for both ionic and non-ionic density forming materials and can be used with data generated from the UV optical system as well as the AVIV fluorescence optical system. These methods have been programmed in a new UltraScan-III module (us_abde). Examples are shown that demonstrate the application of the new module to adeno-associated viral vector preparations and proteins.
- ItemAccurate crystal structures of C12H9CN, C12H8(CN)2, and C16H11CN valence isomers using nonspherical atomic scattering factors(RSC Publishing, 2022) Hill, Nathan D. D.; Lilienthal, Elaura; Bender, Christopher O.; Boeré, René T.Fourteen crystal structures, mostly from good-quality datasets but including some marginal and twinned exemplars, from a series of novel polycyclic benzo- and naphtho-fused organic nitriles are presented and accurately described, including some related structures of a bromo-substituted and partially hydrogenated analogues. These structures represent a considerable increase in the number of published structures within their archetypes. This work highlights the significant advancement in structural refinement software proffered by NoSpherA2, which enables Hirshfeld Atom Refinement (HAR) of the structures within Olex2 v1.5. This results in the determination of C–H bond lengths with near to neutron diffraction accuracies at far lower experimental cost, and with an average improvement in C–C bond precision of 42% compared to Independent Atom Model refinements. H-atoms (apart from disordered components) refined well with anisotropic displacement parameters. Nonclassical H-bonding (C–H···N≡C) in this series is analyzed, and dipolar nitrile–nitrile interactions (C≡N···C≡N) in three major motifs described by (Wood, P. A. Acta Cryst. B, 2008, 64, 393−396) are found in 9 out of 13 nitrile-containing compounds of this series, a much higher proportion than the global average of 21% of nitrile-containing compounds. The HAR/NoSpherA2 approach shows increasing benefits with better data quality without apparent discontinuities.
- ItemAdenine versus guanine DNA adducts of aristolochic acids: role of the carcinogen-purine linkage in the differential global genomic repair propensity(Oxford University Press, 2015) Kathuria, Preetleen; Sharma, Purshotam; Wetmore, Stacey D.Computational modeling is employed to provide a plausible structural explanation for the experimentally-observed differential global genome repair (GGR) propensity of the ALII-N2-dG and ALIIN6- dA DNA adducts of aristolochic acid II. Our modeling studies suggest that an intrinsic twist at the carcinogen–purine linkage of ALII-N2-dG induces lesion site structural perturbations and conformational heterogeneity of damaged DNA. These structural characteristics correlate with the relative repair propensities of AA-adducts, where GGR recognition occurs for ALII-N2-dG, but is evaded for intrinsically planar ALII-N6-dA that minimally distorts DNA and restricts the conformational flexibility of the damaged duplex. The present analysis on the ALII adduct model systems will inspire future experimental studies on these adducts, and thereby may extend the list of structural factors that directly correlate with the propensity for GGR recognition.
- ItemAlternate conformational trajectories in ribosome translocation(Public Library of Science, 2024) Alejo, Jose L.; Girodat, Dylan; Hammerling, Michael J.; Willi, Jessica A.; Jewett, MIchael C.; Engelhart, Aaron E.; Adamala, Katarzyna P.Translocation in protein synthesis entails the efficient and accurate movement of the mRNA-[tRNA]2 substrate through the ribosome after peptide bond formation. An essential conformational change during this process is the swiveling of the small subunit head domain about two rRNA ‘hinge’ elements. Using iterative selection and molecular dynamics simulations, we derive alternate hinge elements capable of translocation in vitro and in vivo and describe their effects on the conformational trajectory of the EF-G-bound, translocating ribosome. In these alternate conformational pathways, we observe a diversity of swivel kinetics, hinge motions, three-dimensional head domain trajectories and tRNA dynamics. By finding alternate conformational pathways of translocation, we identify motions and intermediates that are essential or malleable in this process. These findings highlight the plasticity of protein synthesis and provide a more thorough understanding of the available sequence and conformational landscape of a central biological process.
- ItemAnalysis of the interlink between glucose-6-phosphate dehydrogenase (G6PD) and lung cancer through multi-omics databases(Elsevier, 2024) Thakor, Parth; Siddiqui, M. Quadir; Patel, Trushar R.Glucose-6-Phosphate Dehydrogenase (G6PD) is a crucial enzyme that executes the pentose phosphate pathway. Due to its critical nodal position in the metabolic network, it is associated with different forms of cancer tumorigeneses and progression. Nonetheless, its functional role and molecular mechanism in lung cancer remain unknown. The present study provides intricate information associated with G6PD and Lung Cancer. Varieties of public datasets were retrieved by us, including UALCAN, TCGA, cBioPortal, and the UCSC Xena browser. The data obtained were used to assess the expression of G6PD, its clinical features, epigenetic regulation, relationship with tumour infiltration, tumour mutation burden, microsatellite instability, tumour microenvironment, immune checkpoint genes, genomic alteration, and patient's overall survival rate. The present study revealed that the G6PD expression was correlated with the clinical features of lung cancer including disease stage, race, sex, age, smoking habits, and lymph node metastasis. Moreover, the expression profile of G6PD also imparts epigenetic changes by modulating the DNA promoter methylation activity. Methylation of promoters changes the expression of various transcription factors, genes leading to an influence on the immune system. These events linked with G6PD-related mutational gene alterations (FAM3A, LAG3, p53, KRAS). The entire circumstance influences the patient's overall survival rate and poor prognosis. Functional investigation using STRING, GO, and KEGG found that G6PD primarily engages in hallmark functions (metabolism, immunological responses, proliferation, apoptosis, p53, HIF-1, FOXO, PI3K-AKT signaling). This work provides a wide knowledge of G6PD's function in lung cancer, as well as a theoretical foundation for possible prognostic therapeutic markers.
- ItemApplications and limitations of regulatory RNA elements in synthetic biology and biotechnology(Wiley, 2019) Nshogozabahizi, J. C.; Aubrey, K. L.; Ross, J. A.; Thakor, NehalSynthetic biology requires the design and implementation of novel enzymes, genetic circuits or even entire cells, which can be controlled by the user. RNA‐based regulatory elements have many important functional properties in this regard, such as their modular nature and their ability to respond to specific external stimuli. These properties have led to the widespread exploration of their use as gene regulation devices in synthetic biology. In this review, we focus on two major types of RNA elements: riboswitches and RNA thermometers (RNATs). We describe their general structure and function, before discussing their potential uses in synthetic biology (e.g. in the production of biofuels and biodegradable plastics). We also discuss their limitations, and novel strategies to implement RNA‐based regulatory devices in biotechnological applications. We close with a description of some common model organisms used in synthetic biology, with a focus on the current applications and limitations of RNA‐based regulation.
- ItemArchael proteins Nop10 and Gar1 increase the catalytic activity of Cbf5 in pseudouridylating tRNA(Nature Publishing Group, 2012) Kamalampeta, Rajashekhar; Wieden-Kothe, UteCbf5 is a pseudouridine synthase that usually acts in a guide RNA-dependent manner as part of H/ACA small ribonucleoproteins; however archaeal Cbf5 can also act independently of guide RNA in modifying uridine 55 in tRNA. This guide-independent activity of Cbf5 is enhanced by proteins Nop10 and Gar1 which are also found in H/ACA small ribonucleoproteins. Here, we analyzed the specific contribution of Nop10 and Gar1 for Cbf5-catalyzed pseudouridylation of tRNA. Interestingly, both Nop10 and Gar1 not only increase Cbf5’s affinity for tRNA, but they also directly enhance Cbf5’s catalytic activity by increasing the kcat of the reaction. In contrast to the guide RNA-dependent reaction, Gar1 is not involved in product release after tRNA modification. These results in conjunction with structural information suggest that Nop10 and Gar1 stabilize Cbf5 in its active conformation; we hypothesize that this might also be true for guide-RNA dependent pseudouridine formation by Cbf5.