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Nitric oxide (●NO) participates in many biological activities, including enhancing DNA radiosensitivity in ionizing radiation-based radiotherapy. To help understand the radiosensitization of ●NO, we report reaction dynamics between ●NO and the radical cations of guanine (a 9HG●+ conformer) and 9-methylguanine (9MG●+). On the basis of the formation of 9HG●+ and 9MG●+ in the gas phase and the collisions of the radical cations with ●NO in a guided-ion beam mass spectrometer, the charge transfer reactions of 9HG●+ and 9MG●+ with ●NO were examined. For both reactions, the kinetic energy-dependent product ion cross sections revealed a threshold energy that is 0.24 (or 0.37) eV above the 0 K product 9HG (or 9MG) + NO+ asymptote. To interrogate this abnormal threshold behavior, the reaction potential energy surface for [9MG + NO]+ was mapped out at closed-shell singlet, open-shell singlet, and triplet states using density functional and coupled cluster theories. The results showed that the charge transfer reaction requires the interaction of a triplet-state surface originating from a reactant-like precursor complex 3[9MG●+(↑)⋅(↑)●NO] with a closed-shell singlet-state surface evolving from a charge-transferred complex 1[9MG⋅NO+]. During the reaction, an electron is transferred from π∗(NO) to perpendicular π∗(9MG), which introduces a change in orbital angular momentum. The latter offsets the change in electron spin angular momentum and facilitates intersystem crossing. The reaction threshold in excess of the 0 K thermochemistry and the low charge-transfer efficiency are rationalized by the vibrational excitation in the product ion NO+ and the kinetic shift arising from a long-lived triplet intermediate.

 

It has been shown previously in protonated, deprotonated and ionized guanine–cytosine base pairs that intra-base pair proton transfer from the N1–H at the Watson–Crick edge of guanine to the complementary nucleobase prompts non-statistical dissociation of the base-pair system, and the dissociation of a proton-transferred base-pair structure is kinetically more favored than that of the starting, conventional base-pair structure. However, the fundamental chemistry underlying this anomalous and intriguing kinetics has not been completely revealed, which warrants the examination of more base-pair systems in different structural contexts in order to derive a generalized base-pair structure–kinetics correlation. The purpose of the present work is to expand the investigation to the non-canonical homodimeric and heterodimeric radical cations of 9-methylguanine (9MG) and 9-methyl-8-oxoguanine (9MOG), i.e. , [9MG·9MG]˙ + , [9MOG·9MG]˙ + and [9MOG·9MOG]˙ + . Experimentally, collision-induced dissociation tandem mass spectrometry coupled with an electrospray ionization (ESI) source was used for the formation of base-pair radical cations, followed by detection of dissociation product ions and cross sections in the collisions with Xe gas under single ion–molecule collision conditions and as a function of the center-of-mass collision energy. Computationally, density functional theory and coupled cluster theory were used to calculate and identify probable base-pair structures and intra-base pair proton transfer and hydrogen transfer reactions, followed by kinetics modeling to explore the properties of dissociation transition states and kinetic factors. The significance of this work is twofold: it provides insight into base-pair opening kinetics in three biologically-important, non-canonical systems upon oxidative and ionization damage; and it links non-statistical dissociation to intra-base pair proton-transfer originating from the N1–H at the Watson–Crick edge of 8-oxoguanine, enhancing understanding towards the base-pair fragmentation assisted by proton transfer. 

We investigated the collision-induced dissociation (CID) reactions of a protonated Hoogsteen 9-methylguanine–1-methylcytosine base pair (HG-[9MG·1MC + H] + ), which aims to address the mystery of the literature reported “anomaly” in product ion distributions and compare the kinetics of a Hoogsteen base pair with its Watson-Crick isomer WC-[9MG·1MC + H] + (reported recently by Sun et al. ; Phys. Chem. Chem. Phys. , 2020, 22 , 24986). Product ion cross sections and branching ratios were measured as a function of center-of-mass collision energy using guided-ion beam tandem mass spectrometry, from which base-pair dissociation energies were determined. Product structures and energetics were assessed using various theories, of which the composite DLPNO-CCSD(T)/aug-cc-pVTZ//ωB97XD/6-311++G(d,p) was adopted as the best-performing method for constructing a reaction potential energy surface. The statistical Rice–Ramsperger–Kassel–Marcus theory was found to provide a useful framework for rationalizing the dominating abundance of [1MC + H] + over [9MG + H] + in the fragment ions of HG-[9MG·1MC + H] + . The kinetics analysis proved the necessity for incorporating into kinetics modeling not only the static properties of reaction minima and transition states but more importantly, the kinetics of individual base-pair conformers that have formed in collisional activation. The analysis also pinpointed the origin of the statistical kinetics of HG-[9MG·1MC + H] + vs. the non-statistical behavior of WC-[9MG·1MC + H] + in terms of their distinctively different intra-base-pair hydrogen-bonds and consequently the absence of proton transfer between the N1 position of 9MG and the N3′ of 1MC in the Hoogsteen base pair. Finally, the Hoogsteen base pair was examined in the presence of a water ligand, i.e. , HG-[9MG·1MC + H] + ·H 2 O. Besides the same type of base-pair dissociation as detected in dry HG-[9MG·1MC + H] + , secondary methanol elimination was observed via the S N 2 reaction of water with nucleobase methyl groups.