Excess Electron Interactions with Solvated DNA Nucleotides: Strand Breaks Possible at Room Temperature

Smyth, Maeve; Kohanoff, Jorge

doi:10.1021/ja303776r

Cited by 61 publications

(83 citation statements)

References 32 publications

(70 reference statements)

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“…Figure 26 shows that protonation is favourable for dCMPH − and dTMPH − , and barrier-less for dAMPH − . This helps to explain why adenine spontaneously protonated during unconstrained equilibration in [138], and confirms that it should be in this protonated configuration when in the condensed phase. There are two minima in the free energy profiles for protonation of cytosine and thymine, one where the nucleobase is protonated and one where the hydrogen atom is covalently bonded to a water molecule and hydrogen bonded to the nucleobase.…”

Section: Molecular Dynamics Simulations and Free Energiessupporting

confidence: 61%

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Interactions between low energy electrons and DNA: a perspective from first-principles simulations

Kohanoff¹,

McAllister²,

Tribello³

et al. 2017

J. Phys.: Condens. Matter

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Abstract. DNA damage caused by irradiation has been studied for many decades. Such studies allow us to better assess the dangers posed by radiation, and to increase the efficiency of the radiotherapies that are used to combat cancer. A full description of the irradiation process involves multiple size and time scales. It starts from the interaction of radiation -either photons or swift ions -with the biological medium. Such interactions cause electronic excitation and ionisation. The two main products of ionising radiation are thus electrons and radicals. Both of these species can cause damage to biological molecules, in particular DNA. In the long run, this molecular level damage can prevent cells from replicating and can hence lead to cell death. For a long time it was assumed that the main actors in the damage process were the radicals. However, experiments in a seminal paper by the group of Leon Sanche in 2000 showed that low-energy electrons (LEE), such as those generated when ionising biological targets, can also cause bond breaks in biomolecules, in particular strand breaks in plasmid DNA [1]. These results prompted a significant amount of experimental and theoretical work aimed at elucidating the role played by LEE in DNA damage.In this Topical Review we provide a general overview of the problem. We discuss experimental findings and theoretical results hand in hand with the aim of describing the physics and chemistry that occurs during the process of radiation damage, from the initial stages of electronic excitation, through the inelastic propagation of electrons in the medium, the interaction of electrons with DNA, and the chemical end-point effects on DNA. A very important aspect of this discussion is the consideration of a realistic, physiological environment. The role played by the aqueous solution and the amino acids from the histones in chromatin must be considered. Moreover, thermal fluctuations must be incorporated when studying these phenomena. Hence, a special place in this Topical Review is occupied by our recent first-principles molecular dynamics simulations that address the issue of how the environment favours or prevents LEEs from causing damage to DNA. We finish by summarising the conclusions achieved so far, and by suggesting a number of possible directions for further study.

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Section: Molecular Dynamics Simulations and Free Energiessupporting

confidence: 61%

“…However, when a solute is present the electron localises very rapidly on the nucleobase, over a timescale on the order of 15-25 fs. This fast localisation on the nucleobase was also observed for nucleosides and nucleotides [128,138].…”

Section: Molecular Dynamics Simulations and Free Energiessupporting

confidence: 59%

Interactions between low energy electrons and DNA: a perspective from first-principles simulations

Kohanoff¹,

McAllister²,

Tribello³

et al. 2017

J. Phys.: Condens. Matter

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“…Protonation events are significant as they have been shown to be a competing mechanism to DNA strand breaks 26 . The concept of proton transfer will become important also in the condensed phase as a determination for where the excess electron will be localized.…”

Section: Structurementioning

confidence: 99%

“…Hydrogen bonds, in turn, have been shown to have a stabilising effect on anionic nucleobase structures. This was shown through microsolvation and condensed-phase studies 12,26 , which highlighted proton acceptor sites as particularly able to stablise a structure.…”

Section: Introductionmentioning

confidence: 96%

Protection of DNA against low-energy electrons by amino acids: a first-principles molecular dynamics study

Smyth

Kohanoff

2014

Phys. Chem. Chem. Phys.

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Using first-principles molecular dynamics simulations, we have investigated the notion that amino acids can play a protective role when DNA is exposed to excess electrons produced by ionizing radiation. In this study we focus on the interaction of glycine with the DNA nucleobase thymine. We studied thymineglycine dimers and a condensed phase model consisting of one thymine molecule solvated in amorphous glycine. Our results show that the amino acid acts as a protective agent for the nucleobase in two ways.If the excess electron is initially captured by the thymine, then a proton is transferred in a barrier-less way from a neighboring hydrogen-bonded glycine. This stabilizes the excess electron by reducing the net partial charge on the thymine. In the second mechanism the excess electron is captured by a glycine, which acts as a electron scavenger that prevents electron localization in DNA. Both these mechanisms introduce obstacles to further reactions of the excess electron within a DNA strand, e.g. by raising the free energy barrier associated with strand breaks.

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“…[16i, 20,21] In addition, although the C 3' ÀO 3' bond rupture of dAMP À in explicit water environment was shown to be feasible by an ab initio molecular dynamics simulation, [22] the selfinteraction error tendingt oo verstabilize the delocalized state [20] was not corrected in that work. However, the above-mentioned studies all focused on gasphase or aqueous-phase DNA components, which are inconsistent with the realistic DNA environment in ac ell.…”

Section: Introductionmentioning

confidence: 99%

The Equally Important Role of Adenine Derivatives to That of Pyrimidine Derivatives in Near‐0 eV Electron‐Induced DNA Lesions

et al. 2016

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The role of adenine (A) derivatives in DNA damage is scarcely studied due to the low electron affinity of base A. Experimental studies demonstrate that low-energy electron (LEE) attachment to adenine derivatives complexed with amino acids induces barrier-free proton transfer producing the neutral N7 -hydrogenated adenine radicals rather than conventional anionic species. To explore possible DNA lesions at the A sites under physiological conditions, probable bond ruptures in two models-N7 -hydrogenated 2'-deoxyadenosine-3'-monophosphate (3'-dA(N7H)MPH) and 2'-deoxyadenosine-5'-monophosphate (5'-dA(N7H)MPH), without and with LEE attachment-are studied by DFT. In the neutral cases, DNA backbone breakage and base release resulting from C3' -O3' and N9 -C1' bond ruptures, respectively, by an intramolecular hydrogen-transfer mechanism are impossible due to the ultrahigh activation energies. On LEE attachment, the respective C3' -O3' and N9 -C1' bond ruptures in [3'-dA(N7H)MPH](-) and [5'-dA(N7H)MPH](-) anions via a pathway of intramolecular proton transfer (PT) from the C2' site of 2'-deoxyribose to the C8 atom of the base moiety become effective, and this indicates that substantial DNA backbone breaks and base release can occur at non-3'-end A sites and the 3'-end A site of a single-stranded DNA in the physiological environment, respectively. In particular, compared to the results of previous theoretical studies, not only are the electron affinities of 3'-dA(N7H)MPH and 5'-dA(N7H)MPH comparable to those of hydrogenated pyrimidine derivatives, but also the lowest energy requirements for the C3' -O3' and N9 -glycosidic bond ruptures in [3'-dA(N7H)MPH](-) and [5'-dA(N7H)MPH](-) anions, respectively, are comparable to those for the C3' -O3' and N1 -glycosidic bond cleavages in corresponding anionic hydrogenated pyrimidine derivatives. Thus, it can be concluded that the role of adenine derivatives in single-stranded DNA damage is equally important to that of pyrimidine derivatives in an irradiated cellular environment.

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Excess Electron Interactions with Solvated DNA Nucleotides: Strand Breaks Possible at Room Temperature

Cited by 61 publications

References 32 publications

Interactions between low energy electrons and DNA: a perspective from first-principles simulations

Interactions between low energy electrons and DNA: a perspective from first-principles simulations

Protection of DNA against low-energy electrons by amino acids: a first-principles molecular dynamics study

The Equally Important Role of Adenine Derivatives to That of Pyrimidine Derivatives in Near‐0 eV Electron‐Induced DNA Lesions

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