Intramolecular Proton Transfer in the Radical Anion of Cytidine Monophosphate Sheds Light on the Sensitivities of Dry vs Wet DNA to Electron Attachment-Induced Damage

Abstract

Single-strand breaks (SSBs) induced via electron attachment were previously observed in dry DNA under ultrahigh vacuum (UHV), while hydrated electrons were found not able to induce this DNA damage in an aqueous solution. To explain these findings, crossed electron-molecular beam (CEMB) and anion photoelectron spectroscopy (aPES) experiments coupled to density functional theory (DFT) modeling were used to demonstrate the fundamental importance of proton transfer (PT) in radical anions formed via electron attachment. Three molecular systems were investigated: 5′-monophosphate of 2′-deoxycytidine (dCMPH), where PT in the electron adduct is feasible, and two ethylated derivatives, 5′-diethylphosphate and 3′,5′-tetraethyldiphosphate of 2′-deoxycytidine, where PT is blocked due to substitution of labile protons with the ethyl residues. CEMB and aPES experiments confirmed the cleavage of the C3′/C5′−O bond as the main dissociation channel related to electron attachment in the ethylated derivatives. In the case of dCMPH, however, electron attachment (in the aPES experiments) yielded its parent (intact) radical anion, dCMPH − , suggesting that its dissociation was inhibited. The aPES-measured vertical detachment energy of the dCMPH − was found to be 3.27 eV, which agreed with its B3LYP/6-31++G(d,p)-calculated value and implied that electron-induced proton transfer (EIPT) had occurred during electron attachment to the dCMPH model nucleotide. In other words, EIPT, subduing dissociation, appeared to be somewhat protective against SSB. While EIPT is facilitated in solution compared to the dry environment, the above findings are consistent with the stability of DNA against hydrated electron-induced SSB in solution versus free electron-induced SSB formation in dry DNA.

Surprising Radiolytic Stability of 8-Thiomethyladenine in an Aqueous Solution

“…Indeed, such a protonation enlarges the barrier for electron transfer from the SOMO π orbital of the primary anion to the respective σ* orbital, i.e., for the process that is responsible for electron attachment-induced dissociation. Protonation of radical anions was invoked in the past to explain the hindering of the DEA process in native nucleotides 42 or halo-thiouridines. 43 …”

Prebiotic chemical origin of biomolecular complementarity

“…Alternatively, a hydrogen-donating intermolecular relaxation channel can be opened by the cellular hydrated medium. Experimental evidence that microhydration suppresses vLEE-induced fragmentation of certain nucleobases 49 and the suppression of electron-induced strand break under wet conditions of DNA 50 are relevant here. Although the role of proton transfer has not been attributed to the observed phenomenon, a remarkable inter-moiety proton transfer-assisted suppression of single strand breaks has recently been reported in the literature 50 .…”

“…Experimental evidence that microhydration suppresses vLEE-induced fragmentation of certain nucleobases 49 and the suppression of electron-induced strand break under wet conditions of DNA 50 are relevant here. Although the role of proton transfer has not been attributed to the observed phenomenon, a remarkable inter-moiety proton transfer-assisted suppression of single strand breaks has recently been reported in the literature 50 . The experimental and theoretical demonstration of ICD phenomenon in water 13 , 51 , hydrogen bonded systems 15 , 16 and π -stacked molecules 14 clearly suggests that the UIS mechanisms based on ICD phenomena against multiple assaults can also operate beyond the base pairs.…”

How a Single 5 eV Electron Can Induce Double-Strand Breaks in DNA: A Time-Dependent Density Functional Theory Study

“…To aid in understanding these experiments, − a number of theoretical efforts have been reported for SSB formation and base release, which have helped to unravel the underlying mechanisms. − Mainly, three types of mechanisms of LEE-induced SSB formation in DNA were proposed: (i) Using the Hartree–Fock level of theory, Simons and co-workers proposed a mechanism for SSB formation in which an excess electron primarily attaches to the π* molecular orbital (MO) of the DNA base (shape resonance) and subsequently transfers to the C–O bond region joining the sugar phosphate group, causing the bond to dissociate. Using the B3LYP/DZP++ level of theory, Bao et al also supported Simons’s proposal of SSB formation.…”