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M T Rodgers - One of the best experts on this subject based on the ideXlab platform.
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Amino acid-linked platinum(II) compounds: non-canonical nucleoside preferences and influence on Glycosidic Bond stabilities
JBIC Journal of Biological Inorganic Chemistry, 2019Co-Authors: Bett Kimutai, M T Rodgers, Zhihua Yang, Andrew Roberts, Marcel L. Jones, Xun Bao, Jun Jiang, Christine S. ChowAbstract:Nucleobases serve as ideal targets where drugs bind and exert their anticancer activities. Cisplatin (cisPt) preferentially coordinates to 2′-deoxyguanosine (dGuo) residues within DNA. The dGuo adducts that are formed alter the DNA structure, contributing to inhibition of function and ultimately cancer cell death. Despite its success as an anticancer drug, cisPt has a number of drawbacks that reduce its efficacy, including repair of adducts and drug resistance. Some approaches to overcome this problem involve development of compounds that coordinate to other purine nucleobases, including those found in RNA. In this work, amino acid-linked platinum(II) (AAPt) compounds of alanine and ornithine (AlaPt and OrnPt, respectively) were studied. Their reactivity preferences for DNA and RNA purine nucleosides (i.e., 2′-deoxyadenosine (dAdo), adenosine (Ado), dGuo, and guanosine (Guo)) were determined. The chosen compounds form predominantly monofunctional adducts by reacting at the N1, N3, or N7 positions of purine nucleobases. In addition, features of AAPt compounds that impact the Glycosidic Bond stability of Ado residues were explored. The Glycosidic Bond cleavage is activated differentially for AlaPt-Ado and OrnPt-Ado isomers. Formation of unique adducts at non-canonical residues and subsequent destabilization of the Glycosidic Bonds are important features that could circumvent platinum-based drug resistance. Graphic abstract
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structures and relative Glycosidic Bond stabilities of protonated 2 fluoro substituted purine nucleosides
Journal of the American Society for Mass Spectrometry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and synthetic, can produce biologically valuable nucleoside analogues. The unique properties of fluorine make it particularly interesting and medically useful as a synthetic nucleoside modification. In this work, the effects of 2'-fluoro modification on the protonated gas-phase purine nucleosides are examined using complementary tandem mass spectrometry and computational methods. Direct comparisons are made with previous studies on related nucleosides. Infrared multiple photon dissociation action spectroscopy performed in both the fingerprint and hydrogen-stretching regions allows for the determination of the experimentally populated conformations. The populated conformers of protonated 2'-fluoro-2'-deoxyadenosine, [Adofl+H]+, and 2'-fluoro-2'-deoxyguanosine, [Guofl+H]+, are highly parallel to their respective canonical DNA and RNA counterparts. Both N3 and N1 protonation sites are accessed by [Adofl+H]+, stabilizing syn and anti nucleobase orientations, respectively. N7 protonation and anti nucleobase orientation dominates in [Guofl+H]+. Spectroscopically observable intramolecular hydrogen-Bonding interactions with fluorine allow more definitive sugar puckering determinations than possible for the canonical systems. [Adofl+H]+ adopts C2'-endo sugar puckering, whereas [Guofl+H]+ adopts both C2'-endo and C3'-endo sugar puckering. Energy-resolved collision-induced dissociation experiments with survival yield analyses provide relative Glycosidic Bond stabilities. The N-Glycosidic Bond stabilities of the protonated 2'-fluoro-substituted purine nucleosides are found to exceed those of their canonical analogues. Further, the N-Glycosidic Bond stability is found to increase with increasing electronegativity of the 2'-substituent, i.e., H < OH < F. The N-Glycosidic Bond stability is also greater for the adenine nucleoside analogues than the guanine nucleoside analogues.
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influence of 2 fluoro modification on Glycosidic Bond stabilities and gas phase ion structures of protonated pyrimidine nucleosides
Journal of Fluorine Chemistry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:Abstract The effects of 2′-fluoro substitution on the protonated gas-phase ions of the pyrimidine nucleosides are examined and compared with their previously reported canonical RNA and DNA forms. N-Glycosidic Bond cleavage is the only collision-induced dissociation (CID) fragmentation pathway of protonated 2′-fluoro-2′-deoxycytidine, [Cydfl+H]+, and the major pathway of protonated 2′-fluoro-2′-deoxyuridine, [Urdfl+H]+. Based on energy-resolved CID and survival yield analysis, the N-Glycosidic Bond of [Cydfl+H]+ is more stable than that of [Urdfl+H]+. Further, the N-Glycosidic Bond stability of protonated pyrimidine nucleosides increases with increasing 2′-substituent electronegativity and follows the order F > OH > H. Gas-phase conformations of [Cydfl+H]+ and [Urdfl+H]+ are studied via infrared multiple photon dissociation (IRMPD) action spectroscopy coupled with theoretical calculations. IRMPD action spectra are measured over the IR fingerprint and hydrogen-stretching regions. Comparisons of theoretical and experimental spectra indicate that the experimentally accessed [Cydfl+H]+ and [Urdfl+H]+ conformers are highly parallel to those populated for their canonical counterparts. Evidence for gas-phase intramolecular O3′H⋯F2′ hydrogen-Bonding in the IRMPD spectra of [Cydfl+H]+ and [Urdfl+H]+ allows for more definitive sugar puckering determinations than possible in the analogous canonical nucleosides.
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relative Glycosidic Bond stabilities of naturally occurring methylguanosines 7 methylation is intrinsically activating
European Journal of Mass Spectrometry, 2019Co-Authors: Zachary J Devereaux, Yanlong Zhu, M T RodgersAbstract:The frequency and diversity of posttranscriptional modifications add an additional layer of chemical complexity beyond canonical nucleic acid sequence. Methylations are particularly frequently occurring and often highly conserved throughout the kingdoms of life. However, the intricate functions of these modified nucleic acid constituents are often not fully understood. Systematic foundational research that reduces systems to their minimum constituents may aid in unraveling the complexities of nucleic acid biochemistry. Here, we examine the relative intrinsic N-Glycosidic Bond stabilities of guanosine and five naturally occurring methylguanosines (O2'-, 1-, 7-, N2,N2-di-, and N2,N2,O2'-trimethylguanosine) probed by energy-resolved collision-induced dissociation tandem mass spectrometry and complemented with quantum chemical calculations. Apparent Glycosidic Bond stability is generally found to increase with increasing methyl substitution (canonical < mono- < di- < trimethylated). Many biochemical transformations, including base excision repair mechanisms, involve protonation and/or noncovalent interactions to increase nucleobase leaving-group ability. The protonated gas-phase methylguanosines require less activation energy for Glycosidic Bond cleavage than their sodium cationized forms. However, methylation at the N7 position intrinsically weakens the Glycosidic Bond of 7-methylguanosine more significantly than subsequent cationization, and thus 7-methylguanosine is suggested to be under perpetually activated conditions. N7 methylation also alters the nucleoside geometric preferences relative to the other systems, including the nucleobase orientation in the neutral form, sugar puckering in the protonated form, and the preferred protonation and sodium cation binding sites. All of the methylated guanosines examined here are predicted to have proton affinities and gas-phase basicities that exceed that of canonical guanosine. Additionally, the proton affinity and gas-phase basicity trends exhibit a roughly inverse correlation with the apparent Glycosidic Bond stabilities.
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conformations and n Glycosidic Bond stabilities of sodium cationized 2 deoxycytidine and cytidine solution conformation of cyd na is preserved upon esi
International Journal of Mass Spectrometry, 2018Co-Authors: Yanlong Zhu, L. A. Hamlow, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, Musleh Uddin Munshi, M T RodgersAbstract:Abstract The local structures of DNA and RNA are influenced by protonation, deprotonation and noncovalent interactions with metal cations. In order to determine the effects of sodium cationization on the structures of 2′-deoxycytidine and cytidine, infrared multiple photon dissociation (IRMPD) action spectra of these sodium cationized nucleosides, [dCyd+Na]+ and [Cyd+Na]+, are measured using the FELIX free electron laser and an OPO/OPA laser system. Energy-resolved collision-induced dissociation (ER-CID) experiments for the protonated and sodium cationized forms of the cytosine nucleosides are performed using a Bruker amaZon ETD quadrupole ion trap mass spectrometer (QIT MS) to evaluate the relative propensities of protons and sodium cations for activating the Glycosidic Bonds of the cytosine nucleosides. Complementary electronic structure calculations are performed to determine the stable low-energy conformations of [dCyd + Na]+ and [Cyd + Na]+. For both cytosine nucleosides, theory suggests that tridentate binding of Na+ to the O2, O4′ and O5′ atoms of the cytosine nucleobase and sugar moiety is the most stable binding mode. However, comparison of the measured IRMPD action spectrum and computed linear IR spectra suggests that anti oriented bidentate conformers of [Cyd + Na]+ are predominantly populated in the experiments. The 2′-hydroxyl substituent of Cyd stabilizes the anti oriented bidentate conformers of [Cyd + Na]+, and enables formation of a 2′OH⋯3′OH hydrogen-Bonding interaction. The 2′-hydroxyl substituent is found to stabilize the Glycosidic Bond of Cyd vs. that of dCyd for both the protonated and sodium cationized cytosine nucleosides. Compared to protonation, sodium cationization activates the N-Glycosidic Bond less effectively.
Stacey D. Wetmore - One of the best experts on this subject based on the ideXlab platform.
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Hydrolytic Glycosidic Bond Cleavage in RNA Nucleosides: Effects of the 2'-Hydroxy Group and Acid-Base Catalysis.
Journal of Physical Chemistry B, 2016Co-Authors: Stefan A. P. Lenz, Johnathan D. Kohout, Stacey D. WetmoreAbstract:Despite the inherent stability of Glycosidic linkages in nucleic acids that connect the nucleobases to sugar–phosphate backbones, cleavage of these Bonds is often essential for organism survival. The current study uses DFT (B3LYP) to provide a fundamental understanding of the hydrolytic deglycosylation of the natural RNA nucleosides (A, C, G, and U), offers a comparison to DNA hydrolysis, and examines the effects of acid, base, or simultaneous acid–base catalysis on RNA deglycosylation. By initially examining HCOO–···H2O mediated deglycosylation, the barriers for RNA hydrolysis were determined to be 30–38 kJ mol–1 higher than the corresponding DNA barriers, indicating that the 2′-OH group stabilizes the Glycosidic Bond. Although the presence of HCOO– as the base (i.e., to activate the water nucleophile) reduces the barrier for uncatalyzed RNA hydrolysis (i.e., unactivated H2O nucleophile) by ∼15–20 kJ mol–1, the extreme of base catalysis as modeled using a fully deprotonated water molecule (i.e., OH– nucl...
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Glycosidic Bond cleavage in dna nucleosides effect of nucleobase damage and activation on the mechanism and barrier
Journal of Physical Chemistry B, 2015Co-Authors: Stefan A. P. Lenz, Jennifer L. Kellie, Stacey D. WetmoreAbstract:Although DNA damage can have a variety of deleterious effects on cells (e.g., senescence, death, and rapid growth), the base excision repair (BER) pathway combats the effects by removing several types of damaged DNA. Since the first BER step involves cleavage of the Bond between the damaged nucleobase and the DNA sugar–phosphate backbone, we have used density functional theory to compare the intrinsic stability of the Glycosidic Bond in a number of common DNA oxidation, deamination, and alkylation products to the corresponding natural nucleosides. Our calculations predict that the dissociative (SN1) and associative (SN2) pathways are nearly isoenergetic, with the dissociative pathway only slightly favored on the Gibbs reaction surface for all canonical and damaged nucleosides, which suggests that DNA damage does not affect the inherently most favorable deglycosylation pathway. More importantly, with the exception of thymine glycol, all DNA lesions exhibit reduced Glycosidic Bond stability relative to the ...
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Glycosidic Bond Cleavage in DNA Nucleosides: Effect of Nucleobase Damage and Activation on the Mechanism and Barrier
2015Co-Authors: Stefan A. P. Lenz, Jennifer L. Kellie, Stacey D. WetmoreAbstract:Although DNA damage can have a variety of deleterious effects on cells (e.g., senescence, death, and rapid growth), the base excision repair (BER) pathway combats the effects by removing several types of damaged DNA. Since the first BER step involves cleavage of the Bond between the damaged nucleobase and the DNA sugar–phosphate backbone, we have used density functional theory to compare the intrinsic stability of the Glycosidic Bond in a number of common DNA oxidation, deamination, and alkylation products to the corresponding natural nucleosides. Our calculations predict that the dissociative (SN1) and associative (SN2) pathways are nearly isoenergetic, with the dissociative pathway only slightly favored on the Gibbs reaction surface for all canonical and damaged nucleosides, which suggests that DNA damage does not affect the inherently most favorable deglycosylation pathway. More importantly, with the exception of thymine glycol, all DNA lesions exhibit reduced Glycosidic Bond stability relative to the undamaged nucleosides. Furthermore, the trend in the magnitude of the deglycosylation barrier reduction directly correlates with the relative nucleobase acidity (at N9 for purines or N1 for pyrimidines), which thereby provides a computationally efficient, qualitative measure of the Glycosidic Bond stability in DNA damage. The effect of nucleobase activation (protonation) at different sites predicts that the positions leading to the largest reductions in the deglycosylation barrier are typically used by DNA glycosylases to facilitate base excision. Finally, deaza purine derivatives are found to have greater Glycosidic Bond stability than the canonical counterparts, which suggests that alterations to excision rates measured using these derivatives to probe DNA glycosylase function must be interpreted in reference to the inherent differences in the nucleoside reactivity. Combined with previous studies of the deglycosylation of DNA nucleosides, the current study provides a greater fundamental understanding about the reactivity of the Glycosidic Bond in damaged DNA, which has direct implications to the function of critical DNA repair enzymes
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effects of nucleophile oxidative damage and nucleobase orientation on the Glycosidic Bond cleavage in deoxyguanosine
Journal of Physical Chemistry B, 2010Co-Authors: Eun Jung Shim, Jennifer L Przybylski, Stacey D. WetmoreAbstract:Deglycosylation of nucleotides occurs during many essential biological processes, including DNA repair, and is initiated by a variety of nucleophiles. In the present work, density functional theory (B3LYP) was used to investigate the thermodynamics and kinetics of the Glycosidic Bond cleavage reaction in the model nucleoside forms of guanine and its major oxidation product, 8-oxoguanine. Base excision facilitated by four different nucleophiles (hydroxyl anion (fully activated water), formate-water complex (partially activated water), lysine, and proline) was considered, which spans nucleophiles involved in a collection of spontaneous and enzyme-catalyzed processes. Because some enzymes that catalyze deglycosylation can accommodate more than one orientation of the base with respect to the sugar moiety, the effects of the (anti/syn) base orientation on the barrier height were also considered. We find that the nucleophile has a very large effect on the overall (gas-phase) reaction energetics. Although this effect decreases in different (polar) environments, the nucleophile has the greatest influence on the overall reaction as compared to whether the base is damaged or to the base orientation. Furthermore, the effects are significant in environments that most closely resemble (nonpolar) enzymatic active sites. Our results provide a greater understanding of the relative effects of the nucleophile, damage to the nucleobase, and the nucleobase orientation with respect to the sugar moiety on the deglycosylation pathway, which provide qualitative explanations for relative base excision rates observed in some biological systems.
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Glycosidic Bond cleavage in deoxynucleotides a density functional study
Canadian Journal of Chemistry, 2009Co-Authors: Andrea L Millen, Stacey D. WetmoreAbstract:Density functional theory was used to study the Glycosidic Bond cleavage in deoxynucleotides with the main goal to determine the effects of the nucleobase, hydrogen Bonding with the nucleobase, and...
Narayanaswamy Jayaraman - One of the best experts on this subject based on the ideXlab platform.
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Glycosidic Bond Expanded Cyclic Oligosaccharides: Synthesis and Host-Guest Binding Property of a Cyclic Pentasaccharide.
ACS omega, 2018Co-Authors: Gopal Ch Samanta, Krishnagopal Maiti, Narayanaswamy JayaramanAbstract:A new cyclic pentasaccharide comprising an oxymethylene Glycosidic Bond connecting the individual α-d-glycopyranoside monomers is synthesized through cycloglycosylation of a linear pentasaccharide precursor, which, in turn, is synthesized through the block glycosylation method. Molecular modeling shows that the 30-membered macrocyclic pentasaccharide is a distorted ellipsoid structure, with the lower and upper rims occupied by secondary and primary hydroxyl groups, respectively. Following the synthesis, the microenvironment of the cyclic pentasaccharide is assessed through thermodynamic evaluation upon complexation with 1-aminoadamantane in an aqueous solution, which shows the formation of ∼1:2 host-to-guest complex and a binding affinity of 10 500 (±425) M–1. Synthesis and assessment of the host–guest binding property of the new Glycosidic Bond expanded cyclic pentasaccharide are presented.
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Glycosidic Bond Expanded Cyclic Oligosaccharides: Synthesis and Host–Guest Binding Property of a Cyclic Pentasaccharide
2018Co-Authors: Gopal Ch Samanta, Krishnagopal Maiti, Narayanaswamy JayaramanAbstract:A new cyclic pentasaccharide comprising an oxymethylene Glycosidic Bond connecting the individual α-d-glycopyranoside monomers is synthesized through cycloglycosylation of a linear pentasaccharide precursor, which, in turn, is synthesized through the block glycosylation method. Molecular modeling shows that the 30-membered macrocyclic pentasaccharide is a distorted ellipsoid structure, with the lower and upper rims occupied by secondary and primary hydroxyl groups, respectively. Following the synthesis, the microenvironment of the cyclic pentasaccharide is assessed through thermodynamic evaluation upon complexation with 1-aminoadamantane in an aqueous solution, which shows the formation of ∼1:2 host-to-guest complex and a binding affinity of 10 500 (±425) M–1. Synthesis and assessment of the host–guest binding property of the new Glycosidic Bond expanded cyclic pentasaccharide are presented
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Glycosidic Bond hydrolysis in septanosides a comparison of mono di and 2 chloro 2 deoxy septanosides
Carbohydrate Research, 2014Co-Authors: Supriya Dey, Narayanaswamy JayaramanAbstract:A kinetic study of the hydrolytic stabilities of mono-, di-, and 2-chloro-2-deoxy septanosides, under acid-catalysis, is reported herein. A comparison of mono- and diseptanosides, shows that the Glycosidic Bond in the disaccharide is more stable than the monosaccharide. Further the Glycosidic Bond at the reducing end hydrolyzes almost twice as faster than that of the non-reducing end of the disaccharide. 2-Chloro-2-deoxy septanoside is found to be the most stable and its Glycosidic Bond hydrolysis occurs at elevated temperatures only. The orientation of the exo-cyclic hydroxymethyl group and the inductive effect are suggested to play a role in the rates of hydrolysis.
L. A. Hamlow - One of the best experts on this subject based on the ideXlab platform.
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structures and relative Glycosidic Bond stabilities of protonated 2 fluoro substituted purine nucleosides
Journal of the American Society for Mass Spectrometry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and synthetic, can produce biologically valuable nucleoside analogues. The unique properties of fluorine make it particularly interesting and medically useful as a synthetic nucleoside modification. In this work, the effects of 2'-fluoro modification on the protonated gas-phase purine nucleosides are examined using complementary tandem mass spectrometry and computational methods. Direct comparisons are made with previous studies on related nucleosides. Infrared multiple photon dissociation action spectroscopy performed in both the fingerprint and hydrogen-stretching regions allows for the determination of the experimentally populated conformations. The populated conformers of protonated 2'-fluoro-2'-deoxyadenosine, [Adofl+H]+, and 2'-fluoro-2'-deoxyguanosine, [Guofl+H]+, are highly parallel to their respective canonical DNA and RNA counterparts. Both N3 and N1 protonation sites are accessed by [Adofl+H]+, stabilizing syn and anti nucleobase orientations, respectively. N7 protonation and anti nucleobase orientation dominates in [Guofl+H]+. Spectroscopically observable intramolecular hydrogen-Bonding interactions with fluorine allow more definitive sugar puckering determinations than possible for the canonical systems. [Adofl+H]+ adopts C2'-endo sugar puckering, whereas [Guofl+H]+ adopts both C2'-endo and C3'-endo sugar puckering. Energy-resolved collision-induced dissociation experiments with survival yield analyses provide relative Glycosidic Bond stabilities. The N-Glycosidic Bond stabilities of the protonated 2'-fluoro-substituted purine nucleosides are found to exceed those of their canonical analogues. Further, the N-Glycosidic Bond stability is found to increase with increasing electronegativity of the 2'-substituent, i.e., H < OH < F. The N-Glycosidic Bond stability is also greater for the adenine nucleoside analogues than the guanine nucleoside analogues.
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influence of 2 fluoro modification on Glycosidic Bond stabilities and gas phase ion structures of protonated pyrimidine nucleosides
Journal of Fluorine Chemistry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:Abstract The effects of 2′-fluoro substitution on the protonated gas-phase ions of the pyrimidine nucleosides are examined and compared with their previously reported canonical RNA and DNA forms. N-Glycosidic Bond cleavage is the only collision-induced dissociation (CID) fragmentation pathway of protonated 2′-fluoro-2′-deoxycytidine, [Cydfl+H]+, and the major pathway of protonated 2′-fluoro-2′-deoxyuridine, [Urdfl+H]+. Based on energy-resolved CID and survival yield analysis, the N-Glycosidic Bond of [Cydfl+H]+ is more stable than that of [Urdfl+H]+. Further, the N-Glycosidic Bond stability of protonated pyrimidine nucleosides increases with increasing 2′-substituent electronegativity and follows the order F > OH > H. Gas-phase conformations of [Cydfl+H]+ and [Urdfl+H]+ are studied via infrared multiple photon dissociation (IRMPD) action spectroscopy coupled with theoretical calculations. IRMPD action spectra are measured over the IR fingerprint and hydrogen-stretching regions. Comparisons of theoretical and experimental spectra indicate that the experimentally accessed [Cydfl+H]+ and [Urdfl+H]+ conformers are highly parallel to those populated for their canonical counterparts. Evidence for gas-phase intramolecular O3′H⋯F2′ hydrogen-Bonding in the IRMPD spectra of [Cydfl+H]+ and [Urdfl+H]+ allows for more definitive sugar puckering determinations than possible in the analogous canonical nucleosides.
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conformations and n Glycosidic Bond stabilities of sodium cationized 2 deoxycytidine and cytidine solution conformation of cyd na is preserved upon esi
International Journal of Mass Spectrometry, 2018Co-Authors: Yanlong Zhu, L. A. Hamlow, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, Musleh Uddin Munshi, M T RodgersAbstract:Abstract The local structures of DNA and RNA are influenced by protonation, deprotonation and noncovalent interactions with metal cations. In order to determine the effects of sodium cationization on the structures of 2′-deoxycytidine and cytidine, infrared multiple photon dissociation (IRMPD) action spectra of these sodium cationized nucleosides, [dCyd+Na]+ and [Cyd+Na]+, are measured using the FELIX free electron laser and an OPO/OPA laser system. Energy-resolved collision-induced dissociation (ER-CID) experiments for the protonated and sodium cationized forms of the cytosine nucleosides are performed using a Bruker amaZon ETD quadrupole ion trap mass spectrometer (QIT MS) to evaluate the relative propensities of protons and sodium cations for activating the Glycosidic Bonds of the cytosine nucleosides. Complementary electronic structure calculations are performed to determine the stable low-energy conformations of [dCyd + Na]+ and [Cyd + Na]+. For both cytosine nucleosides, theory suggests that tridentate binding of Na+ to the O2, O4′ and O5′ atoms of the cytosine nucleobase and sugar moiety is the most stable binding mode. However, comparison of the measured IRMPD action spectrum and computed linear IR spectra suggests that anti oriented bidentate conformers of [Cyd + Na]+ are predominantly populated in the experiments. The 2′-hydroxyl substituent of Cyd stabilizes the anti oriented bidentate conformers of [Cyd + Na]+, and enables formation of a 2′OH⋯3′OH hydrogen-Bonding interaction. The 2′-hydroxyl substituent is found to stabilize the Glycosidic Bond of Cyd vs. that of dCyd for both the protonated and sodium cationized cytosine nucleosides. Compared to protonation, sodium cationization activates the N-Glycosidic Bond less effectively.
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Structural and Energetic Effects of O2′-Ribose Methylation of Protonated Purine Nucleosides
2018Co-Authors: L. A. Hamlow, Y. Zhu, Zachary J Devereaux, Y.-w. Nei, L. Fan, C. P. Mcnary, P. Maitre, V. Steinmetz, B. SchindlerAbstract:The chemical difference between DNA and RNA nucleosides is their 2′-hydrogen versus 2′-hydroxyl substituents. Modification of the ribosyl moiety at the 2′-position and 2′-O-methylation in particular, is common among natural post-transcriptional modifications of RNA. 2′-Modification may alter the electronic properties and hydrogen-Bonding characteristics of the nucleoside and thus may lead to enhanced stabilization or malfunction. The structures and relative Glycosidic Bond stabilities of the protonated forms of the 2′-O-methylated purine nucleosides, 2′-O-methyladenosine (Adom) and 2′-O-methylguanosine (Guom), were examined using two complementary tandem mass spectrometry approaches, infrared multiple photon dissociation action spectroscopy and energy-resolved collision-induced dissociation. Theoretical calculations were also performed to predict the structures and relative stabilities of stable low-energy conformations of the protonated forms of the 2′-O-methylated purine nucleosides and their infrared spectra in the gas phase. Low-energy conformations highly parallel to those found for the protonated forms of the canonical DNA and RNA purine nucleosides are also found for the protonated 2′-O-methylated purine nucleosides. Importantly, the preferred site of protonation, nucleobase orientation, and sugar puckering are preserved among the DNA, RNA, and 2′-O-methylated variants of the protonated purine nucleosides. The 2′-substituent does however influence hydrogen-Bond stabilization as the 2′-O-methyl and 2′-hydroxyl substituents enable a hydrogen-Bonding interaction between the 2′- and 3′-substituents, whereas a 2′-hydrogen atom does not. Further, 2′-O-methylation reduces the number of stable low-energy hydrogen-Bonded conformations possible and importantly inverts the preferred polarity of this interaction versus that of the RNA analogues. Trends in the CID50% values extracted from survival yield analyses of the 2′-O-methylated and canonical DNA and RNA forms of the protonated purine nucleosides are employed to elucidate their relative Glycosidic Bond stabilities. The Glycosidic Bond stability of Adom is found to exceed that of its DNA and RNA analogues. The Glycosidic Bond stability of Guom is also found to exceed that of its DNA analogue; however, this modification weakens this Bond relative to its RNA counterpart. The Glycosidic Bond stability of the protonated purine nucleosides appears to be correlated with the hydrogen-Bond stabilization of the sugar moiety
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Gas-Phase Conformations and N‑Glycosidic Bond Stabilities of Sodium Cationized 2′-Deoxyguanosine and Guanosine: Sodium Cations Preferentially Bind to the Guanine Residue
2017Co-Authors: Y. Zhu, J Oomens, L. A. Hamlow, J. K. Lee, J. Gao, G. Berden, M T RodgersAbstract:2′-Deoxyguanosine (dGuo) and guanosine (Guo) are fundamental building blocks of DNA and RNA nucleic acids. In order to understand the effects of sodium cationization on the gas-phase conformations and stabilities of dGuo and Guo, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and complementary electronic structure calculations are performed. The measured IRMPD spectra of [dGuo+Na]+ and [Guo+Na]+ are compared to calculated IR spectra predicted for the stable low-energy structures computed for these species to determine the most favorable sodium cation binding sites, identify the structures populated in the experiments, and elucidate the influence of the 2′-hydroxyl substituent on the structures and IRMPD spectral features. These results are compared with those from a previous IRMPD study of the protonated guanine nucleosides to elucidate the differences between sodium cationization and protonation on structure. Energy-resolved collision-induced dissociation (ER-CID) experiments and survival yield analyses of protonated and sodium cationized dGuo and Guo are performed to compare the effects of these cations toward activating the N-Glycosidic Bonds of these nucleosides. For both [dGuo+Na]+ and [Guo+Na]+, the gas-phase structures populated in the experiments are found to involve bidentate binding of the sodium cation to the O6 and N7 atoms of guanine, forming a 5-membered chelation ring, with guanine found in both anti and syn orientations and C2′-endo (2T3 or 3T2) puckering of the sugar. The ER-CID results, IRMPD yields and the computed C1′–N9 Bond lengths indicate that sodium cationization activates the N-Glycosidic Bond less effectively than protonation for both dGuo and Guo. The 2′-hydroxyl substituent of Guo is found to impact the preferred structures very little except that it enables a 2′OH···3′OH hydrogen Bond to be formed, and stabilizes the N-Glycosidic Bond relative to that of dGuo in both the sodium cationized and protonated complexes
Giel Berden - One of the best experts on this subject based on the ideXlab platform.
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structures and relative Glycosidic Bond stabilities of protonated 2 fluoro substituted purine nucleosides
Journal of the American Society for Mass Spectrometry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:The 2'-substituent is the primary distinguishing feature between DNA and RNA nucleosides. Modifications to this critical position, both naturally occurring and synthetic, can produce biologically valuable nucleoside analogues. The unique properties of fluorine make it particularly interesting and medically useful as a synthetic nucleoside modification. In this work, the effects of 2'-fluoro modification on the protonated gas-phase purine nucleosides are examined using complementary tandem mass spectrometry and computational methods. Direct comparisons are made with previous studies on related nucleosides. Infrared multiple photon dissociation action spectroscopy performed in both the fingerprint and hydrogen-stretching regions allows for the determination of the experimentally populated conformations. The populated conformers of protonated 2'-fluoro-2'-deoxyadenosine, [Adofl+H]+, and 2'-fluoro-2'-deoxyguanosine, [Guofl+H]+, are highly parallel to their respective canonical DNA and RNA counterparts. Both N3 and N1 protonation sites are accessed by [Adofl+H]+, stabilizing syn and anti nucleobase orientations, respectively. N7 protonation and anti nucleobase orientation dominates in [Guofl+H]+. Spectroscopically observable intramolecular hydrogen-Bonding interactions with fluorine allow more definitive sugar puckering determinations than possible for the canonical systems. [Adofl+H]+ adopts C2'-endo sugar puckering, whereas [Guofl+H]+ adopts both C2'-endo and C3'-endo sugar puckering. Energy-resolved collision-induced dissociation experiments with survival yield analyses provide relative Glycosidic Bond stabilities. The N-Glycosidic Bond stabilities of the protonated 2'-fluoro-substituted purine nucleosides are found to exceed those of their canonical analogues. Further, the N-Glycosidic Bond stability is found to increase with increasing electronegativity of the 2'-substituent, i.e., H < OH < F. The N-Glycosidic Bond stability is also greater for the adenine nucleoside analogues than the guanine nucleoside analogues.
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influence of 2 fluoro modification on Glycosidic Bond stabilities and gas phase ion structures of protonated pyrimidine nucleosides
Journal of Fluorine Chemistry, 2019Co-Authors: Zachary J Devereaux, L. A. Hamlow, Yanlong Zhu, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, M T RodgersAbstract:Abstract The effects of 2′-fluoro substitution on the protonated gas-phase ions of the pyrimidine nucleosides are examined and compared with their previously reported canonical RNA and DNA forms. N-Glycosidic Bond cleavage is the only collision-induced dissociation (CID) fragmentation pathway of protonated 2′-fluoro-2′-deoxycytidine, [Cydfl+H]+, and the major pathway of protonated 2′-fluoro-2′-deoxyuridine, [Urdfl+H]+. Based on energy-resolved CID and survival yield analysis, the N-Glycosidic Bond of [Cydfl+H]+ is more stable than that of [Urdfl+H]+. Further, the N-Glycosidic Bond stability of protonated pyrimidine nucleosides increases with increasing 2′-substituent electronegativity and follows the order F > OH > H. Gas-phase conformations of [Cydfl+H]+ and [Urdfl+H]+ are studied via infrared multiple photon dissociation (IRMPD) action spectroscopy coupled with theoretical calculations. IRMPD action spectra are measured over the IR fingerprint and hydrogen-stretching regions. Comparisons of theoretical and experimental spectra indicate that the experimentally accessed [Cydfl+H]+ and [Urdfl+H]+ conformers are highly parallel to those populated for their canonical counterparts. Evidence for gas-phase intramolecular O3′H⋯F2′ hydrogen-Bonding in the IRMPD spectra of [Cydfl+H]+ and [Urdfl+H]+ allows for more definitive sugar puckering determinations than possible in the analogous canonical nucleosides.
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conformations and n Glycosidic Bond stabilities of sodium cationized 2 deoxycytidine and cytidine solution conformation of cyd na is preserved upon esi
International Journal of Mass Spectrometry, 2018Co-Authors: Yanlong Zhu, L. A. Hamlow, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, Musleh Uddin Munshi, M T RodgersAbstract:Abstract The local structures of DNA and RNA are influenced by protonation, deprotonation and noncovalent interactions with metal cations. In order to determine the effects of sodium cationization on the structures of 2′-deoxycytidine and cytidine, infrared multiple photon dissociation (IRMPD) action spectra of these sodium cationized nucleosides, [dCyd+Na]+ and [Cyd+Na]+, are measured using the FELIX free electron laser and an OPO/OPA laser system. Energy-resolved collision-induced dissociation (ER-CID) experiments for the protonated and sodium cationized forms of the cytosine nucleosides are performed using a Bruker amaZon ETD quadrupole ion trap mass spectrometer (QIT MS) to evaluate the relative propensities of protons and sodium cations for activating the Glycosidic Bonds of the cytosine nucleosides. Complementary electronic structure calculations are performed to determine the stable low-energy conformations of [dCyd + Na]+ and [Cyd + Na]+. For both cytosine nucleosides, theory suggests that tridentate binding of Na+ to the O2, O4′ and O5′ atoms of the cytosine nucleobase and sugar moiety is the most stable binding mode. However, comparison of the measured IRMPD action spectrum and computed linear IR spectra suggests that anti oriented bidentate conformers of [Cyd + Na]+ are predominantly populated in the experiments. The 2′-hydroxyl substituent of Cyd stabilizes the anti oriented bidentate conformers of [Cyd + Na]+, and enables formation of a 2′OH⋯3′OH hydrogen-Bonding interaction. The 2′-hydroxyl substituent is found to stabilize the Glycosidic Bond of Cyd vs. that of dCyd for both the protonated and sodium cationized cytosine nucleosides. Compared to protonation, sodium cationization activates the N-Glycosidic Bond less effectively.
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effects of sodium cationization versus protonation on the conformations and n Glycosidic Bond stabilities of sodium cationized urd and durd solution conformation of urd na is preserved upon esi
Physical Chemistry Chemical Physics, 2017Co-Authors: Yanlong Zhu, S. F. Strobehn, J. Gao, H A Roy, N A Cunningham, Giel Berden, Jos Oomens, Musleh Uddin Munshi, M T RodgersAbstract:Uridine (Urd) is one of the naturally occurring pyrimidine nucleosides of RNA. 2′-Deoxyuridine (dUrd) is a naturally occurring modified form of Urd, but is not one of the canonical DNA nucleosides. In order to understand the effects of sodium cationization on the conformations and energetics of Urd and dUrd, infrared multiple photon dissociation (IRMPD) action spectroscopy experiments and density functional theory (DFT) calculations are performed. By comparing the calculated IR spectra of [Urd+Na]+ and [dUrd+Na]+ with the measured IRMPD spectra, the stable low-energy conformers populated in the experiments are determined. Anti oriented bidentate O2 and O2′ binding conformers of [Urd+Na]+ are the dominant conformers populated in the experiments, whereas syn oriented tridentate O2, O4′, and O5′ binding conformers of [dUrd+Na]+ are dominantly populated in the experiments. The 2′-hydroxyl substituent of Urd stabilizes the anti oriented O2 binding conformers of [Urd+Na]+. Significant differences between the measured IRMPD and calculated IR spectra for complexes of [Urd+Na]+ and [dUrd+Na]+ involving minor tautomeric forms of the nucleobase make it obvious that none are populated in the experiments. Survival yield analyses based on energy-resolved collision-induced dissociation (ER-CID) experiments suggest that the relative stabilities of protonated and sodium cationized Urd and dUrd follow the order: [dUrd+H]+ < [Urd+H]+ < [dUrd+Na]+ < [Urd+Na]+. The 2′-deoxy modification is found to weaken the Glycosidic Bond of dUrd versus that of Urd for the sodium cationized uridine nucleosides.
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influence of sodium cationization versus protonation on the gas phase conformations and Glycosidic Bond stabilities of 2 deoxyadenosine and adenosine
Journal of Physical Chemistry B, 2016Co-Authors: L. A. Hamlow, S. F. Strobehn, Giel Berden, Jos Oomens, C C He, M T RodgersAbstract:The influence of noncovalent interactions with a sodium cation on the gas-phase structures and N-Glycosidic Bond stabilities of 2′-deoxyadenosine (dAdo) and adenosine (Ado), [dAdo+Na]+ and [Ado+Na]+, are probed via infrared multiple photon dissociation (IRMPD) action spectroscopy and energy-resolved collision-induced dissociation (ER-CID) experiments. ER-CID experiments are also performed on the protonated forms of these nucleosides, [dAdo+H]+ and [Ado+H]+, for comparison purposes. Complementary electronic structure calculations are performed to determine the structures and relative stabilities of the stable low-energy conformations of the sodium cationized nucleoside complexes and to predict their IR spectra. Comparison between the measured IRMPD action spectra and calculated IR spectra enables the conformations of the sodium cationized nucleosides present in the experiments to be elucidated. The influence of sodium cationization versus protonation on the structures and IR spectra is elucidated by compar...
