Mechanism of the OH Radical Addition to Adenine from Quantum-Chemistry Determinations of Reaction Paths and Spectroscopic Tracking of the Intermediates

The OH radical is a well-known mediator in the oxidation of biological structures like DNA. Over the past decades, the precise events taking place after reaction of DNA nucleobases with OH radical have been widely investigated by the scientific community. Thirty years after the proposal of the main routes for the reaction of ^•OH with adenine (Vieira, A.; Steenken, S. J. Am. Chem. Soc. 1990, 112, 6986−6994), the present work demonstrates that the OH radical addition to C4 position is a minor pathway. Instead, the dehydration process is mediated by the A5OH adduct. Conclusions are based on density functional theory calculations for the ground-state reactivity and highly accurate multiconfigurational computations for the excited states of the radical intermediates. The methodology has been also used to study the mechanism giving rise to the mutagens 8-oxoA and FAPyA. Taking into account the agreement between the experimental data and the theoretical results, it is concluded that addition to the C5 and C8 positions accounts for at least ∼44.5% of the total ^•OH reaction in water solution. Finally, the current findings suggest that hydrophobicity in the DNA/RNA surroundings facilitates the formation of 8-oxoA and FAPyA

Theoretical Study of the Hydroxyl Radical Addition to Uracil and Photochemistry of the Formed U6OH^• Adduct

Hydroxyl radical (^•OH) is produced in biological systems by external or endogenous agents. It can damage DNA/RNA by attacking pyrimidine nucleobases through the addition to the C5C6 double bond. The adduct resulting from the attachment at the C5 position prevails in the experimental measurements, although the reasons for this preference remain unclear. The first aim of this work is therefore to shed light on the comprehension of this important process. Thus, the thermal ^•OH addition to the C5C6 double bond of uracil has been studied theoretically by using DFT, MP2, and the multiconfigurational CASPT2//CASSCF methodologies. The in-vacuo results obtained with the latter protocol plus the analysis of solvent effects support the experimental observation. A significant lower barrier height is predicted for the C5 pathway with respect to that of the C6 route. In contrast to the C5 adduct, the C6 adduct is able to absorb visible light. Hence, the second aim of the work is to study the photochemistry of this species using the CASPT2//CASSCF methodology within the framework of the photochemical reaction path approach (PRPA). The nonradiative decay to the ground state of this compound has been characterized. A photoreactive character is predicted for the C6 adduct in the excited states according to the presence of excited-state minima along the main decay channel. Finally, a new mechanism of photodissociation has been explored, which implies the photoinduced regeneration of the canonical nucleobase by irradiating with visible light, being therefore relevant in RNA protection against damage by reactive oxygen species

Relaxation Mechanisms of 5‑Azacytosine

The photophysics and deactivation pathways of the noncanonical 5-azacytosine nucleobase were studied using the CASPT2//CASSCF protocol. One of the most significant differences with respect to the parent molecule cytosine is the presence of a dark ¹(<i>n</i>_Nπ*) excited state placed energetically below the bright excited state ¹(ππ*) at the Franck–Condon region. The main photoresponse of the system is a presumably efficient radiationless decay back to the original ground state, mediated by two accessible conical intersections involving a population transfer from the ¹(ππ*) and the ¹(<i>n</i>_Nπ*) states to the ground state. Therefore, a minor contribution of the triplet states in the photophysics of the system is expected, despite the presence of a deactivation path leading to the lowest ³(ππ*) triplet state. The global scenario on the photophysics and photochemistry of the 5-azacytosine system gathered on theoretical grounds is consistent with the available experimental data, taking especially into account the low values of the singlet–triplet intersystem crossing and fluorescence quantum yields observed

Cyclobutane Pyrimidine Photodimerization of DNA/RNA Nucleobases in the Triplet State

The photoinduced formation of cyclobutane pyrimidine dimers in the triplet excited state of the DNA/RNA pyrimidine nucleobases pairs has been studied at the CASPT2 level of theory. A stepwise mechanism through the triplet state of the homodimer is proposed for the pairs of nucleobases cytosine, thymine, and uracil involving a singlet−triplet crossing intermediary structure of biradical character representing the most favorable triplet state conformation of the nucleobases as found in the DNA environment. The efficiency of the mechanism will be modulated by two factors: the effectiveness of the triplet−triplet energy transfer process from a donor photosensitizer molecule, which relates to the relative position of the intermediate in the three acceptor systems, determined here to be lower in energy in the thymine and uracil dimers than in the cytosine pairs, and that of the intersystem crossing process toward the ground state of the photoproduct

Photoinduced Formation Mechanism of the Thymine–Thymine (6–4) Adduct

The photoinduced mechanism leading to the formation of the thymine–thymine (6–4) photolesion has been studied by using the CASPT2//CASSCF approach over a dinucleotide model in vacuo. Following light absorption, localization of the excitation on a single thymine leads to fast singlet–triplet crossing that populates the triplet ³(nπ*) state of thymine. This state, displaying an elongated C₄O bond, triggers (6–4) dimer formation by reaction with the C₅C₆ double bond of the adjacent thymine, followed by a second intersystem crossing, which acts as a gate between the excited state of the reactant and the ground state of the photoproduct. The requirement of localized excitation on just one thymine, whose main decay channel (by radiationless repopulation of its ground state) is nonphotochemical, can rationalize the experimentally observed low quantum yield of formation for the thymine–thymine (6–4) adduct

On the N₁–H and N₃–H Bond Dissociation in Uracil by Low Energy Electrons: A CASSCF/CASPT2 Study

The dissociative electron-attachment (DEA) phenomena at the N₁–H and N₃–H bonds observed experimentally at low energies (<3 eV) in uracil are studied with the CASSCF/CASPT2 methodology. Two valence-bound π^– and two dissociative σ^– states of the uracil anionic species, together with the ground state of the neutral molecule, are proven to contribute to the shapes appearing in the experimental DEA cross sections. Conical intersections (CI) between the π^– and σ^– are established as the structures which activate the DEA processes. The N₁–H and N₃–H DEA mechanisms in uracil are described, and experimental observations are interpreted on the basis of two factors: (1) the relative energy of the (U–H)⁻ + H fragments obtained after DEA with respect to the ground-state equilibrium structure (S₀) of the neutral molecule (threshold for DEA) and (2) the relative energy of the CIs also with respect to S₀ (band maxima). The π₁^– state is found to be mainly responsible for the N₁–H bond breaking, whereas the π₂^– state is proved to be involved in the cleavage of the N₃–H bond

On the Deactivation Mechanisms of Adenine–Thymine Base Pair

In this contribution, the multiconfigurational second-order perturbation theory method based on a complete active space reference wave function (CASSCF/CASPT2) is applied to study all possible single and double proton/hydrogen transfers between the nucleobases in the adenine–thymine (AT) base pair, analyzing the role of excited states with different nature [localized (LE) and charge transfer (CT)], and considering concerted as well as step-wise mechanisms. According to the findings, once the lowest excited states, localized in adenine, are populated during UV irradiation of the Watson–Crick base pair, the proton transfer in the N–O bridge does not require high energy in order to populate a CT state. The latter state will immediately relax toward a crossing with the ground state, which will funnel the system to either the canonical structure or the imino–enol tautomer. The base pair is also capable of repairing itself easily since the imino–enol species is unstable to thermal conversion

Tuning the Photophysical Properties of <i>anti</i>-B₁₈H₂₂: Efficient Intersystem Crossing between Excited Singlet and Triplet States in New 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀.

The tuning of the photophysical properties of the highly fluorescent boron hydride cluster <i>anti</i>-B₁₈H₂₂ (<b>1</b>), by straightforward chemical substitution to produce 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀ (<b>2</b>), facilitates intersystem crossing from excited singlet states to a triplet manifold. This subsequently enhances O₂(¹Δ_g) singlet oxygen production from a quantum yield of Φ_Δ ∼ 0.008 in <b>1</b> to 0.59 in <b>2</b>. This paper describes the synthesis and full structural characterization of the new compound 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀ (<b>2</b>) and uses UV–vis spectroscopy coupled with density functional theory (DFT) and ab initio computational studies to delineate and explain its photophysical properties

Tuning the Photophysical Properties of <i>anti</i>-B₁₈H₂₂: Efficient Intersystem Crossing between Excited Singlet and Triplet States in New 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀.

The tuning of the photophysical properties of the highly fluorescent boron hydride cluster <i>anti</i>-B₁₈H₂₂ (<b>1</b>), by straightforward chemical substitution to produce 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀ (<b>2</b>), facilitates intersystem crossing from excited singlet states to a triplet manifold. This subsequently enhances O₂(¹Δ_g) singlet oxygen production from a quantum yield of Φ_Δ ∼ 0.008 in <b>1</b> to 0.59 in <b>2</b>. This paper describes the synthesis and full structural characterization of the new compound 4,4′-(HS)₂-<i>anti</i>-B₁₈H₂₀ (<b>2</b>) and uses UV–vis spectroscopy coupled with density functional theory (DFT) and ab initio computational studies to delineate and explain its photophysical properties

Proton/Hydrogen Transfer Mechanisms in the Guanine–Cytosine Base Pair: Photostability and Tautomerism

Proton/hydrogen-transfer processes have been broadly studied in the past 50 years to explain the photostability and the spontaneous tautomerism in the DNA base pairs. In the present study, the CASSCF/CASPT2 methodology is used to map the two-dimensional potential energy surfaces along the stretched NH reaction coordinates of the guanine–cytosine (GC) base pair. Concerted and stepwise pathways are explored initially <i>in vacuo</i>, and three mechanisms are studied: the stepwise double proton transfer, the stepwise double hydrogen transfer, and the concerted double proton transfer. The results are consistent with previous findings related to the photostability of the GC base pair, and a new contribution to tautomerism is provided. The C-based imino-oxo and imino-enol GC tautomers, which can be generated during the UV irradiation of the Watson–Crick base pair, have analogous radiationless energy-decay channels to those of the canonical base pair. In addition, the C-based imino-enol GC tautomer is thermally less stable. A study of the GC base pair is carried out subsequently taking into account the DNA surroundings in the biological environment. The most important stationary points are computed using the quantum mechanics/molecular mechanics (QM/MM) approach, suggesting a similar scenario for the proton/hydrogen-transfer phenomena <i>in vacuo</i> and in DNA. Finally, the static model is complemented by <i>ab initio</i> dynamic simulations, which show that vibrations at the hydrogen bonds can indeed originate hydrogen-transfer processes in the GC base pair. The relevance of the present findings for the rationalization of the preservation of the genetic code and mutagenesis is discussed