Gas-phase formation and reactions of radical cations of guanosine, deoxyguanosine and their homodimers and heterodimers☆
Graphical abstract
Investigation of the gas-phase formation and reactions of radical cations of guanosine, deoxyguanosine and their homodimers and heterodimers has revealed a novel tautomeric structure, illustrated above, that may have important biological implications.
Introduction
Metal ions and metal complexes bind to nucleic acids at a range of different sites [1], [2], [3], [4], [5], [6], [7], [8], and can also promote supramolecular complex formation via hydrogen bonding and/or base stacking interactions [9], [10], [11], [12], [13], [14], [15], [16], [17]. Electrospray ionisation (ESI) mass spectrometry of mixtures of metal ions/metal complexes and nucleic acids has proven to be a useful way of uncovering such supramolecular complexes (for a recent review on ESI/MS of metal ion-nucleic acid complexes, see [18]). For example, ESI of solutions of silver(I) and the nucleobase adenine resulted in the formation of polymeric silver adenine clusters of the type [Adx + Agy − zH](y−z)+ [19], [20]. Guanine (G) and its derivatives exhibit a diverse range of supramolecular architectures in the condensed phase, including alkali earth metal templated tetramers, A, and “ribbon” structures, B [9], [10], [11]. ESI mass spectrometry studies of guanine and its derivatives have also revealed a range of complexes, some of which exhibit “magic numbers” [21], [22], [23], [24], [25], [26]. An example of such a magic number is the well-known guanosine quartet, which has been observed to assemble around various cations including NH4+ and alkali metal cations [12], [13], [14], [15], [16], [17]. ESI of mixtures of either deoxyguanosine (dG, C1) or guanosine (Gs, C2) and transition metals often yields a range of complexes of different stoichiometry, and the gas-phase chemistry of mass-selected complexes can be dependant on the size and nature of the complex. For example, the collision-induced dissociation (CID) spectra of [PtIILdGn]2+ complexes (where L = 2,2′:6′,2″ terpyridine, terpy, or diethyltriamine, dien) give primary fragmentation channels arising from loss of dG and protonated dG to yield the fragment ions [PtIILdGn−x]2+ and [PtIILdGn−x-H]+, respectively [26]. The relative abundances of the [PtIILdGn−x]2+ fragments depend on the nature of the ligand, L, with the most abundant peaks being observed for n − x = 5 when L = terpy and n − x = 4 when L = dien. When a redox active metal such as Cu(II) is used, Cheng and Bohme have shown that monomeric and dimeric radical cations of guanosine, Gs, can be formed via CID of [CuIIGsn]2+ complexes [25]. This contrasts with previous studies on the fragmentation of copper ternary complexes, [CuIILdG]2+ (L = 2,2′:6′,2″ terpyridine, terpy, or diethyltriamine, dien), where cleavage of the N-glycosidic bond occurred in preference to loss of the radical cation [24]. Cheng and Bohme found that the fragmentation of the [CuIIGsn]2+ complexes is size dependant [25]. When n = 2, loss of the protonated nucleoside (Eq. (4)) and cleavage of N-glycosidic bond (Eqs. (6), (7)) occurs. With n = 3, the complexes undergo only charge separation with formation of the monomeric radical cation (Eq. (1)). And with n = 4, the fragmentation entails the loss of the neutral nucleoside (Eq. (3)) and formation of the dimeric radical cation (Eq. (2)).[CuIIGsn]2+ → [CuIIGsn−1]+ + Gs+[CuIIGsn]2+ → [CuIIGsn−2]+ + Gs2+[CuIIGsn]2+ → [CuIIGsn−1]2+ + Gs[CuIIGsn]2+ → [CuIIGsn−2(Gs-H)]+ + GsH+[CuIIGsn]2+ → [CuIIGsn−3(Gs-H)]+ + Gs2H+[CuIIGsn]2+ → [CuIIGsn−1G]2+ + R-H[CuIIGsn]2+ → [CuII(Gsn−1G)-H]+ + R+
Nucleobases recognise one another by specific patterns of hydrogen bonding. Besides the Watson–Crick pairing observed in DNA, a number of non-Watson–Crick/non-canonical hydrogen-bonding motifs have been found to mediate RNA–RNA interactions and create binding sites for proteins and small molecule ligands [27]. It is not clear, however, what roles hydrogen bonding and tautomerism have on the assembly of metal complexes of guanine and its derivatives via ESI/MS and how these factors might influence their subsequent gas-phase chemistry. Thus, here we examine: (i) the CID reactions of a range of homo ([CuIIdGn]2+ and [CuIIGsn]2+) and hetero [CuIIdGnGsm]2+ complexes; (ii) the fragmentation reactions of the monomeric nucleoside radical cations; (iii) the fragmentation reactions of the nucleoside homodimeric and heterodimeric radical cations; (iv) possible structures of the dimer radical cation for the model 9-methylguanine (9-MeG, C3). Our results suggest an unusual mode of base pairing that plays a role in the formation and fragmentation chemistry of nucleoside dimeric radical cations.
Section snippets
Experimental
All reagents were used as supplied: Cu(NO3)2 (Ajax chemicals, 99%), guanosine hydrate (Aldrich, 98%) and deoxyguanosine (Sigma, 99%). Complexes were prepared by mixing 2:1 mM solutions of the nucleosides:Cu(NO3)2, dissolved in 3:1 methanol:water, right before infusing the reaction mixture into the mass spectrometer.
Results and discussion
ESI of mixtures of the nucleosides incubated with Cu(NO3)2 resulted in the formation of a range of ions and an illustrative spectrum is shown for dG in Fig. 1. The types of ions formed included the radical cation and protonated nucleoside and the doubly charged copper nucleoside complexes [CuIIdGn]2+, where n ranges from 2 to 10. Other complexes of high relative abundance present in the ESI spectrum include [Cu(dGG)-H]+ (m/z 480), CudG+ (m/z 597) and [CudG3-H]+ (m/z 863).
Conclusions
Upon ESI, dG and Gs form gas-phase doubly charged copper nucleoside complexes; [CuIIdGn]2+ and [CuIIGsn]2+ (2 ≤ n ≤ 10). Depending on the size of the cluster, n, different fragmentation pathways can be observed upon CID. For example, in the case of dG, monomeric radical cations are formed via redox processes when n = 3, while when n = 4, dimeric radical cations are formed. The latter also generate monomer radical cations upon an additional stage of CID. The key experimental finding in this work is that
Acknowledgements
RAJO and LF thank the ARC for financial support via the ARC Centre of Excellence in Free Radical Chemistry and Biotechnology. LF thanks the ARC for the award of an APD. The authors gratefully acknowledge the generous allocation of computing time from the Victorian Partnership for Advanced Computing (VPAC) Facility.
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Part 73 of the series “Gas-Phase Ion Chemistry of Biomolecules”.