Wetmore, Stacey
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- ItemStructural and energetic characterization of the major DNA adduct formed from the food mutagen ochratoxin A in the NarI hotspot sequence: influence of adduct ionization on the conformational preferences and implications for the NER propensity(Oxford University Press, 2014) Sharma, Purshotam; Manderville, Richard A.; Wetmore, Stacey D.The nephrotoxic food mutagen ochratoxin A (OTA) produces DNA adducts in rat kidneys, the major lesion being the C8-linked-2 -deoxyguanosine adduct (OTB-dG). Although research on other adducts stresses the importance of understanding the structure of the associated adducted DNA, site-specific incorporation of OTB-dG into DNA has yet to be attempted. The present work uses a robust computational approach to determine the conformational preferences of OTB-dG in three ionization states at three guanine positions in the NarI recognition sequence opposite cytosine. Representative adducted DNA helices were derived from over 2160 ns of simulation and ranked via free energies. For the first time, a close energetic separation between three distinct conformations is highlighted, which indicates OTA-adducted DNA likely adopts a mixture of conformations regardless of the sequence context. Nevertheless, the preferred conformation depends on the flanking bases and ionization state due to deviations in discrete local interactions at the lesion site. The structural characteristics of the lesion thus discerned have profound implications regarding its repair propensity andmutagenic outcomes, and support recent experiments suggesting the induction of double-strand breaks and deletion mutations upon OTA exposure. This combined structural and energetic characterization of the OTB-dG lesion in DNA will encourage future biochemical experiments on this potentially genotoxic lesion.
- ItemStructural and biochemical impact of C8-aryl-guanine adducts within the Narl recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity(Oxford University Press, 2014) Sproviero, Michael; Verwey, Anne M. R.; Rankin, Katherine M.; Witham, Aaron A.; Soldatov, Dmitriy V.; Manderville, Richard A.; Fekry, Mostafa I.; Sturla, Shana J.; Sharma, Purshotam; Wetmore, Stacey D.Chemical mutagens with an aromatic ring system may be enzymatically transformed to afford aryl radical species that preferentially react at the C8-site of 2 -deoxyguanosine (dG). The resulting carbonlinked C8-aryl-dG adduct possesses altered biophysical and genetic coding properties compared to the precursor nucleoside. Described herein are structural and in vitro mutagenicity studies of a series of fluorescent C8-aryl-dG analogues that differ in aryl ring size and are representative of authentic DNA adducts. These structural mimics have been inserted into a hotspot sequence for frameshift mutations, namely, the reiterated G3-position of the NarI sequence within 12mer (NarI(12)) and 22mer (NarI(22)) oligonucleotides. In the NarI(12) duplexes, the C8- aryl-dG adducts display a preference for adopting an anti-conformation opposite C, despite the strong syn preference of the free nucleoside. Using the NarI(22) sequence as a template for DNA synthesis in vitro, mutagenicity of the C8-aryl-dG adducts was assayed with representative high-fidelity replicative versus lesion bypass Y-family DNA polymerases, namely, Escherichia coli pol I Klenow fragment exo− (Kf−) and Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). Our experiments provide a basis for a model involving a two-base slippage and subsequent realignment process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical structures.
- ItemDNA-protein pi-interactions in nature: abundance, structure, composition and strength of contacts between aromatic amino acids and DNA neucleobases or deoxyribose sugar(Oxford University Press, 2014) Wilson, Katie A.; Kellie, Jennifer L.; Wetmore, Stacey D.Four hundred twenty-eight high-resolution DNA– protein complexes were chosen for a bioinformatics study. Although 164 crystal structures (38% of those searched) contained no interactions, 574 discrete pi- contacts between the aromatic amino acids and the DNA nucleobases or deoxyribose were identified using strict criteria, including visual inspection. The abundance and structure of the interactions were determined by unequivocally classifying the contacts as either pi–pi stacking, Pi–pi T-shaped or sugar– pi contacts. Three hundred forty-four nucleobase– amino acid pi–pi contacts (60% of all interactions identified) were identified in 175 of the crystal structures searched. Unprecedented in the literature, 230 DNA–protein sugar–pi contacts (40% of all interactions identified) were identified in 137 crystal structures, which involve C–H···pi and/or lone–pair···pi interactions, contain any amino acid and can be classified according to sugar atoms involved. Both pi–pi and sugar–pi interactions display a range of relative monomer orientations and therefore interaction energies (up to –50 (–70) kJ mol−1 for neutral (charged) interactions as determined using quantum chemical calculations). In general, DNA–protein pi-interactions are more prevalent than perhaps currently accepted and the role of such interactions in many biological processes may yet to be uncovered.
- 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.
- ItemComputational evaluation of nucleotide insertion opposite expanded and widened DNA by the translesion synthesis polymerase Dpo4(M D P I A G, 2016) Albrecht, Laura; Wilson, Katie A.; Wetmore, Stacey D.Expanded (x) and widened (y) deoxyribose nucleic acids (DNA) have an extra benzene ring incorporated either horizontally (xDNA) or vertically (yDNA) between a natural pyrimidine base and the deoxyribose, or between the 5- and 6-membered rings of a natural purine. Far-reaching applications for (x,y)DNA include nucleic acid probes and extending the natural genetic code. Since modified nucleobases must encode information that can be passed to the next generation in order to be a useful extension of the genetic code, the ability of translesion (bypass) polymerases to replicate modified bases is an active area of research. The common model bypass polymerase DNA polymerase IV (Dpo4) has been previously shown to successfully replicate and extend past a single modified nucleobase on a template DNA strand. In the current study, molecular dynamics (MD) simulations are used to evaluate the accommodation of expanded/widened nucleobases in the Dpo4 active site, providing the first structural information on the replication of (x,y)DNA. Our results indicate that the Dpo4 catalytic (palm) domain is not significantly impacted by the (x,y)DNA bases. Instead, the template strand is displaced to accommodate the increased C1’–C1’ base-pair distance. The structural insights unveiled in the present work not only increase our fundamental understanding of Dpo4 replication, but also reveal the process by which Dpo4 replicates (x,y)DNA, and thereby will contribute to the optimization of high fidelity and efficient polymerases for the replication of modified nucleobases.
- ItemSyntheses and characterization of W(NC6F5)F5– and W2(NC6F5)2F9– salts and computational studies of the W(NR)F5– (R = H, F, CH3, CF3, C6H5, C6F5) and W2(NC6F5)2F9– anions(American Chemical Society, 2017) Turnbull, Douglas; Wetmore, Stacey D.; Gerken, MichaelConvenient preparative routes to fluorido[(pentafluorophenyl)imido]tungstate(VI) salts have been developed. The reaction of WF6·NC5H5 or [N(CH3)4][WF7] with C6F5NH2 results in quantitative formation of the C5H5NH+ or N(CH3)4+ salt of the W(NC6F5)F5– anion, respectively. The dissolution of [C5H5NH][W(NC6F5)F5] in anhydrous HF results in the formation of [C5H5NH][W2(NC6F5)2F9]. These salts have been comprehensively characterized in the solid state by X-ray crystallography and Raman spectroscopy and in solution by 19F and 1H NMR spectroscopy. The crystal structures of the W(NC6F5)F5– salts reveal conformational differences in the anions, and the 19F NMR spectra of these salts in CH3CN reveal coupling of the axial fluorido ligand to the 14N nucleus of the imido ligand. In addition, density functional theory (DFT-B3LYP) calculations have been performed on a series of W(NR)F5– anions (R = H, F, CH3, CF3, C6H5, C6F5) and the W2(NC6F5)2F9– anion, including gas-phase geometry optimizations, vibrational frequencies, molecular orbitals, and natural bond orbital (NBO) analyses.
- ItemSolid-state structure of a protonated ketones and aldehydes(Wiley, 2017) Stuart, Daniel; Wetmore, Stacey D.; Gerken, MichaelProtonated carbonyl compounds have been invoked as intermediates in many acid-catalyzed organic reactions. To gain key structural and electronic data about such intermediates, oxonium salts derived from five representative examples of ketones and aldehydes are synthesized in the solid state, and characterized by X-ray crystallography and Raman spectroscopy for the first time. DFT calculations were carried out on the cations in the gas phase. Whereas an equimolar reaction of the carbonyl compounds, acetone, cyclopentanone, adamantanone, and acetaldehyde, with SbF5 in anhydrous HF yielded mononuclear oxonium cations, the same stoichiometry in a reaction with benzaldehyde resulted in formation of a hemiprotonated, hydrogen-bridged dimeric cation. Hemiprotonated acetaldehyde was obtained when a 2:1 ratio of aldehyde and SbF5 was used. Experimental and NBO analyses quantify the significant increase in electrophilicity of the oxonium cations compared to that of the parent ketones/aldehydes.
- ItemSyntheses, characterisation, and computational studies of tungsten hexafluoride adducts with pyridine and its derivatives(Elsevier, 2018) Turnbull, Douglas; Kostiuk, Nathan; Wetmore, Stacey D.; Gerken, MichaelThe reactions of WF6 with pyridine, 4-methylpyridine, 4-(dimethylamino)pyridine, and 4,4′-bipyridine (4,4′-bipy) in CH2Cl2 afford the Lewis-acid-base adducts WF6(4-NC5H4R) (R = H, CH3, N(CH3)2) and F6W(4,4′-bipy)WF6 as solids in quantitative yields. These adducts have been characterised in the solid state by Raman spectroscopy at ambient temperature and, in the cases of the mononuclear adducts, by X-ray crystallography at −173 °C. Furthermore, density-functional-theory (DFT-B3LYP) studies have been conducted to aid in predicting the structure of F6W(4,4′-bipy)WF6, assigning the vibrational frequencies of the adducts, and comparing their electronic properties.
- ItemSyntheses, characterization, and computational study of AsF5 adducts with ketones(Elsevier, 2019) Stuart, Daniel; Wetmore, Stacey D.; Gerken, MichaelLewis acid-base adducts between AsF5 and the ketones, acetone, cyclopentanone, and adamantanone, were synthesized from SO2 and CH2Cl2 solutions. These adducts, which contain O---As pnictogen bonding interactions, were found to be stable in solutions at room temperature. Raman and NMR spectroscopy of the solid adducts showed a characteristic decrease in the C=O stretching frequency, as well as dramatic deshielding of the 13C resonance of the carbonyl group upon adduct formation. Fluorine-19 NMR spectroscopy showed the two fluorine environments of the O–AsF5 moiety. Optimization of the gas-phase geometry using DFT calculations yielded geometries with essentially planar CC=OAs moieties. NBO analyses of the adducts and the free ketones show the polarization of the C=O bond upon adduct formation. The lowering of the LUMO energies upon adduct formation is more dramatic than what was found for protonation of ketones and reflects the substantially enhanced electrophilicity of the adducted ketones.
- ItemSynthesis, characterization, and Lewis acid behavior of [W(NC6F5)F4]x and computational study of W(NR)F4 (R = H, F, CH3, CF3, C6H5, C6F5), W(NC6F5)F4(NCCH3), and W(NC6F5)F4(NC5H5)n (n = 1, 2)(American Chemical Society, 2019) Turnbull, Douglas; Wetmore, Stacey D.; Gerken, MichaelAmorphous [W(NC6F5)F4]x has been synthesized by the reaction of [C5H5NH][W(NC6F5)F5] with AsF5 in CH2Cl2. The reaction of [W(NC6F5)F4]x with CH3CN yields monomeric W(NC6F5)F4(NCCH3), whereas reaction with a sub-2-fold excess of C5H5N in CH3CN results in quantitative conversion to W(NC6F5)F4(NC5H5). Meanwhile, the reaction of W(NC6F5)F4(NCCH3) with a large excess of C5H5N results in the precipitation of W(NC6F5)F4(NC5H5)2. These compounds have been characterized in the solid state by Raman spectroscopy and in solution by multinuclear NMR spectroscopy. The crystal structures of W(NC6F5)F4(NCCH3) and W(NC6F5)F4(NC5H5), as well as improved structures of WOF4(NC5H5)n (n = 1, 2), have been obtained at low temperatures. Furthermore, density functional theory (DFT-B3LYP) calculations have been conducted on the W(NR)F4 (R = H, F, CH3, CF3, C6H5, C6F5) series as well as W(NC6F5)F4(NCCH3) and W(NC6F5)F4(NC5H5)n (n = 1, 2), providing optimized gas-phase geometries, vibrational frequencies, molecular orbitals, fluoride-ion affinities, and natural bond orbital (NBO) analyses.
- ItemStabilization of [WF5]+ by bidentate N-donor ligands(Wiley, 2019) Turnbull, Douglas; Wetmore, Stacey D.; Gerken, MichaelTransition-metal hexafluorides do not exhibit fluoride-ion donor properties in the absence of donor ligands. We report the first synthesis of donor-stabilized [MF5]+ derived from a transition-metal hexafluoride via fluoride-ion abstraction using WF6(L) (L=2,2′-bipy, 1,10-phen) and SbF5(OSO) in SO2. The [WF5(L)][Sb2F11] salts and [WF5(1,10-phen)][SbF6]⋅SO2 have been characterized by X-ray crystallography, Raman spectroscopy, and multinuclear NMR spectroscopy. The reaction of WF6(2,2′-bipy) with an equimolar amount of SbF5(OSO) reveals an equilibrium between [WF5(2,2′-bipy)]+ and the [WF4(2,2′-bipy)2]2+ dication, as determined by 19F NMR spectroscopy. The geometries of the cations in the solid state are reproduced by gas-phase geometry optimizations (DFT-B3LYP), and NBO analyses reveal that the positive charges of the cations are stabilized primarily by compensatory σ-electron donation from the N-donor ligands.
- ItemReactions of molybdenum and tungsten oxide tetrafluoride with sulfur(IV) Lewis bases: structure and bonding in [WOF4]4, MOF4(OSO), and [SF3][M2O2F9] (M = Mo, W)(American Chemical Society, 2020) Turnbull, Douglas; Chaudhary, Praveen; Leenstra, Dakota; Hazendonk, Paul; Wetmore, Stacey D.The structure of [WOF4]4 has been reinvestigated by low-temperature X-ray crystallography and DFT (MN15/def2- SVPD) studies. Whereas the W4F4 ring of the tetramer is planar and disordered in the solid state, the optimized gas-phase geometry prefers a disphenoidally puckered W4F4 ring and demonstrates asymmetric fluorine bridging. Dissolution of MOF4 (M = Mo, W) in SO2 and SF4 results in the formation of MOF4(OSO) and [SF3][M2O2F9], respectively. Both SO2 adducts and [SF3]- [Mo2O2F9] have been characterized by X-ray crystallography. The crystal structure of [SF3][Mo2O2F9] reveals dimerization of the ion pair that results in a rare heptacoordinate sulfur center. Optimization of the {[SF3][M2O2F9]}2 dimers in the gas phase, however, results in the elongation of one contact such that the sulfur centers are effectively hexacoordinate. Meanwhile, the crystal structure of [SF3][W2O2F9]·HF instead demonstrates hexacoordinate sulfur centers and a highly unusual coordination to [SF3]+ from [W2O2F9]−through an oxido ligand. While [SF3][W2O2F9] does not decompose at ambient temperature, MOF4(OSO) and [SF3][Mo2O2F9] are unstable toward evolution of SO2 or SF4. Computational studies reveal that the monomerization of [WOF4]4 in the gas phase at 25 °C is thermodynamically unfavorable using SO2, but favorable using SF4, consistent with the relative thermal stabilities of WOF4(OSO) and [SF3][W2O2F9].
- ItemStabilisation of [WF5]+ and WF5 by pyridine: facile access to [WF5(NC5H5)3]+ and WF5(NC5H5)2(Wiley, 2020) Turnbull, Douglas; Hazendonk, Paul; Wetmore, Stacey D.The enhanced reactivity of [WF5]+ over WF6 has been exploited to access a neutral derivative of elusive WF5. The reaction of WF6(NC5H5)2 with [(CH3)3Si(NC5H5)][O3SCF3] in CH2Cl2 results in quantitative formation of trigonal-dodecahedral [WF5(NC5H5)3]+, which has been characterised as its [O3SCF3]− salt by Raman spectroscopy in the solid state and variable-temperature NMR spectroscopy in solution. The salt is susceptible to slow decomposition in solution at ambient temperature via dissociation of a pyridyl ligand, and the resultant [WF5(NC5H5)2]+ is reduced to WF5(NC5H5)2 in the presence of excess C5H5N, as determined by 19F NMR spectroscopy. Pentagonal-bipyramidal WF5(NC5H5)2 was isolated and characterised by X-ray crystallography and Raman spectroscopy in the solid state, representing the first unambiguously characterised WF5 adduct, as well as the first heptacoordinate adduct of a transition-metal pentafluoride. DFT-B3LYP methods have been used to investigate the reduction of [WF5(NC5H5)2]+ to WF5(NC5H5)2, supporting a two-electron reduction of WVI to WIV by nucleophilic attack and diprotonation of a pyridyl ligand in the presence of free C5H5N, followed by comproportionation to WV.
- ItemChalcogen versus dative bonding in [SF3] + Lewis acid−base adducts: [SF3(NCCH3)2] +, [SF3(NC5H5)2] +, and [SF3(phen)]+ (phen = 1,10-phenanthroline)(American Chemical Society, 2021) Turnbull, Douglas; Chaudhary, Praveen; Hazendonk, Paul; Wetmore, Stacey D.; Gerken, MichaelThe Lewis-acid behavior of [SF3][MF6] (M = Sb, As) salts toward mono- and bidentate nitrogen bases was explored. Reactions of [SF3][MF6] with excesses of CH3CN and C5H5N yielded [SF3(L)2]+ (L = CH3CN, C5H5N) salts, whereas the reaction of [SF3][SbF6] with equimolar 1,10-phenanthroline (phen) in CH3CN afforded [SF3(phen)][SbF6]·2CH3CN. Salts of these cations were characterized by low-temperature X-ray crystallography and Raman spectroscopy in the solid state as well as by 19F NMR spectroscopy in solution. In the solid state, the geometries of [SF3(NC5H5)2]+ and [SF3(phen)]+ are square pyramids with negligible cation–anion contacts, whereas the coordination of CH3CN and [SbF6]− to [SF3]+ in [SF3(NCCH3)2][SbF6] results in a distorted octahedral coordination sphere with a minimal perturbation of the trigonal-pyramidal SF3 moiety. 19F NMR spectroscopy revealed that [SF3(L)2]+ is fluxional in excess L at −30 °C, whereas [SF3(phen)]+ is rigid in CH2Cl2 at −40 °C. Density functional theory (DFT-B3LYP) calculations suggest that the S–N bonds in [SF3(NC5H5)2]+ and [SF3(phen)]+ possess substantial covalent character and result in a regular AX5E VSEPR geometry, whereas those in [SF3(NCCH3)2]+ are best described as S···N chalcogen-bonding interactions via σ-holes on [SF3]+, which is consistent with the crystallographic data.
- ItemLewis acid behavior of MoF5 and MoOF4: syntheses and characterization of MoF5(NCCH3), MoF5(NC5H5)n, and MoOF4(NC5H5)n (n- 1, 2)(ACS Publications, 2021) Bykowski, Janelle; Turnbull, Douglas; Hahn, Nolan R. J.; Boeré, René T.; Wetmore, Stacey D.; Gerken, MichaelThe Lewis acid–base adducts MoF5(NC5H5)n and MoOF4(NC5H5)n (n = 1, 2) were synthesized from the reactions of MoF5 and MoOF4 with C5H5N and structurally characterized by X-ray crystallography. Whereas the crystal structures of MoF5(NC5H5)2 and MoOF4(NC5H5)2 are isomorphous containing pentagonal-bipyramidal molecules, the fluorido-bridged, heptacoordinate [MoF5(NC5H5)]2 dimer differs starkly from monomeric, hexacoordinate MoOF4(NC5H5). For the weaker Lewis base CH3CN, only the 1:1 adduct, MoF5(NCCH3), could be isolated. All adducts were characterized by Raman spectroscopy in conjunction with vibrational frequency calculations. Multinuclear NMR spectroscopy revealed an unprecedented isomerism of MoOF4(NC5H5)2 in solution, with the pyridyl ligands occupying adjacent or nonadjacent positions in the equatorial plane of the pentagonal bipyramid. Paramagnetic MoF5(NC5H5)2 was characterized by electron paramagnetic resonance (EPR) spectroscopy as a dispersion in solid adamantane as well as in a diamagnetic host lattice of MoOF4(NC5H5)2; EPR parameters were computed using ZORA with the BPW91 functional using relativistic all-electron wave functions for Mo and simulated using EasySpin. Density functional theory calculations (B3LYP) and natural bond orbital analyses were conducted to elucidate the distinctive bonding and structural properties of all adducts reported herein and explore fundamental differences observed in the Lewis acid behavior of MoF5 and MoOF4.