Repetitive nucleic acid sequences, which occur in abundance throughout the mammalian genome, are of enormous research interest due to their potential to adopt fascinating and unusual molecular structures such as the i-motif. In remarkable contrast to the DNA double helix, i-motif conformations are stabilized by protonated cytosine base pairs, (Cyt)H + (Cyt), that are centrally located in the core of the i-motif and intercalated vertically in an antiparallel fashion. An in-depth understanding of how modifications influence the stability of i-motif conformations is a prerequisite to understanding their biological functions and the development of effective means of tuning their stability for specific medical and technological applications. Here, the influence of the 2′-and 3′-hydroxy substituents of the sugar moieties and 5-methylation of the cytosine nucleobases on the base-pairing interactions of protonated cytidine nucleoside analogue base pairs, (xCyd)H + (xCyd), are examined by complementary threshold collision-induced dissociation techniques and computational methods. The xCyd nucleosides examined include the canonical DNA and RNA cytidine nucleosides, 2′-deoxycytidine (dCyd) and cytidine (Cyd), as well as several modified cytidine nucleoside analogues, 2′,3′-dideoxycytidine (ddCyd), 5-methyl-2′-deoxycytidine (m 5 dCyd), and 5-methylcytidine (m 5 Cyd). Comparisons among these model base pairs indicate that the 2′-and 3′-hydroxy substituents of the sugar moieties have very little influence on the strength of the base-pairing interactions, whereas 5-methylation of the cytosine nucleobases is found to enhance the strength of the base-pairing interactions. The increase in stability resulting from 5-methylation is only modest but is more than twice as large for the DNA than RNA protonated cytidine base pair. Overall, present results suggest that canonical DNA i-motif conformations should be more stable than analogous RNA i-motif conformations and that 5-methylation of cytosine residues, a significant epigenetic marker, provides greater stabilization to DNA than RNA i-motif conformations.

Ionic liquids (ILs) have become increasingly popular due to their useful and unique properties, yet there are still many unanswered questions regarding their fundamental interactions. In particular, details regarding the nature and strength of the intrinsic cation–anion interactions and how they influence the macroscopic properties of ILs are still largely unknown. Elucidating the molecular-level details of these interactions is essential to the development of better models for describing ILs and enabling the purposeful design of ILs with properties tailored for specific applications. Current uses of ILs are widespread and diverse and include applications for energy storage, electrochemistry, designer/green solvents, separations, and space propulsion. To advance the understanding of the energetics, conformations, and dynamics of gas-phase IL clustering relevant to space propulsion, threshold collision-induced dissociation approaches are used to measure the bond dissociation energies (BDEs) of the 2:1 clusters of 1-alkyl-3-methylimidazolium cations and tetrafluoroborate, [2C n mim:BF4]+. The cation, [C n mim]+, is varied across the series, 1-ethyl-3-methylimidazolium [C2mim]+, 1-butyl-3-methylimidazolium [C4mim]+, 1-hexyl-3-methylimidazolium [C6mim]+, and 1-octyl-3-methylimidazolium [C8mim]+, to examine the structural and energetic effects of the size of the 1-alkyl substituent on binding. Complementary electronic structure calculations are performed to determine the structures and energetics of the [C n mim]+ and [BF4]− ions and their binding preferences in the (C n mim:BF4) ion pairs and [2C n mim:BF4]+ clusters. Several levels of theory, B3LYP, B3LYP-GD3BJ, and M06-2X, using the 6-311+G­(d,p) basis set for geometry optimizations and frequency analyses and the 6-311+G­(2d,2p) basis set for energetics, are benchmarked to examine their abilities to properly describe the nature of the binding interactions and to reproduce the measured BDEs. The modest structural variation among these [C n mim]+ cations produces only minor structural changes and variation in the measured BDEs of the [2C n mim:BF4]+ clusters. Present findings indicate that the dominant cation–anion interactions involve the 3-methylimidazolium moieties and that these clusters are sufficiently small that differences in packing effects associated with the variable length of the 1-alkyl substituents are not yet significant.

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Cisplatin, (NH3)2PtCl2, has been known as a successful metal-based anticancer drug for more than half a century. Its analogue, Argplatin, arginine-linked cisplatin, (Arg)PtCl2, is being investigated because it exhibits reactivity...

Thymidine (dThd) is a fundamental building block of DNA nucleic acids, whereas 5-methyluridine (Thd) is a common modified nucleoside found in tRNA. In order to determine the conformations of the sodium cationized thymine nucleosides [dThd+Na] and [Thd+Na] produced by electrospray ionization, their infrared multiple photon dissociation (IRMPD) action spectra are measured. Complementary electronic structure calculations are performed to determine the stable low-energy conformations of these complexes. Geometry optimizations and frequency analyses are performed at the B3LYP/6-311+G(d,p) level of theory, whereas energies are calculated at the B3LYP/6-311+G(2d,2p) level of theory. As protonation preferentially stabilizes minor tautomers of dThd and Thd, tautomerization facilitated by Na binding is also considered. Comparisons of the measured IRMPD and computed IR spectra find that [dThd+Na] prefers tridentate (O2,O4',O5') coordination to the canonical 2,4-diketo form of dThd with thymine in a syn orientation. In contrast, [Thd+Na] prefers bidentate (O2,O2') coordination to the canonical 2,4-diketo tautomer of Thd with thymine in an anti orientation. Although 2,4-dihydroxy tautomers and O2 protonated thymine nucleosides coexist in the gas phase, no evidence for minor tautomers is observed for the sodium cationized species. Consistent with experimental observations, the computational results confirm that the sodium cationized thymine nucleosides exhibit a strong preference for the canonical form of the thymine nucleobase. Survival yield analyses based on energy-resolved collision-induced dissociation (ER-CID) experiments suggest that the relative stabilities of protonated and sodium cationized dThd and Thd follow the order [dThd+H] < [Thd+H] < [dThd+Na] < [Thd+Na]. Graphical Abstract ᅟ.

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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Modified nucleosides have been an important target for pharmaceutical development for the treatment of cancer, herpes simplex virus, and the human immunodeficiency virus (HIV). Amongst these nucleoside analogues, those based on 2′,3′-dideoxyribose sugars are quite common, particularly in anti-HIV applications. The gas-phase structures of several protonated 2′,3′-dideoxyribose nucleosides are examined in this work and compared with those of the analogous protonated DNA, RNA, and arabinose nucleosides to elucidate the influence of the 2′-and combined 2′,3′-hydroxyl groups on intrinsic structure. Infrared multiple photon dissociation (IRMPD) action spectra are collected for the protonated 2′,3′-dideoxy forms of adenosine, guanosine, cytidine, thymidine and uridine, [ddAdo+H] + , [ddGuo+H] + , [ddCyd+H] + , [ddThd+H] + , and [ddUrd+H] + , in the IR fingerprint and hydrogen-stretching regions. Molecular mechanics conformational searching followed by electronic structure calculations generates low-energy conformers of the protonated 2′,3′dideoxynucleosides and corresponding predicted linear IR spectra to facilitate interpretation of the measured IRMPD action spectra. These experimental IRMPD spectra and theoretical calculations indicate that the absence of the 2′-and 3′-hydroxyls largely preserves the protonation preferences of the canonical forms. The spectra and calculated structures indicate a slight preference for C3′-endo sugar puckering. The presence of the 3′-and further 2′-hydroxyl increases the available intramolecular hydrogen-bonding opportunities and shifts the sugar puckering modes for all nucleosides but the guanosine analogues to a slight preference for C2′-endo over C3′-endo.