Ab initio determination of the electron affinities of DNA and RNA nucleobases

High-level quantum-chemical ab initio coupled-cluster and multiconfigurational perturbation methods have been used to compute the vertical and adiabatic electron affinities of the five canonical DNA and RNA nucleobases: uracil, thymine, cytosine, adenine, and guanine. The present results aim for the accurate determination of the intrinsic electron acceptor properties of the isolated nucleic acid bases as described by their electron affinities, establishing an overall set of theoretical reference values at a level not reported before and helping to rule out less reliable theoretical and experimental data and to calibrate theoretical [email protected] [email protected] [email protected] [email protected]

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

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

Revisiting the Nonadiabatic Process in 1,2-Dioxetane

Determining the ground and excited-state decomposition mechanisms of 1,2-dioxetane is essential to understand the chemiluminescence and bioluminescence phenomena. Several experimental and theoretical studies has been performed in the past without reaching a converged description. The reason is in part associated with the complex nonadiabatic process taking place along the reaction. The present study is an extension of a previous work (De Vico, L.; Liu, Y.-J.; Krogh, J. W.; Lindh, R. <i>J. Phys. Chem. A</i> <b>2007</b>, <i>111</i>, 8013–8019) in which a two-step mechanism was established for the chemiluminescence involving asynchronous O–O′ and C–C′ bond dissociations. New high-level multistate multi configurational reference second-order perturbation theory calculations and <i>ab initio</i> molecular dynamics simulations at constant temperature are performed in the present study, which provide further details on the mechanisms and allow to rationalize further experimental observations. In particular, the new results explain the high ratio of triplet to singlet dissociation products

Regioselectivity of the OH Radical Addition to Uracil in Nucleic Acids. A Theoretical Approach Based on QM/MM Simulations

Oxidation of nucleic acids is ubiquitous in living beings under metabolic impairments and/or exposed to external agents such as radiation, pollutants, or drugs, playing a central role in the development of many diseases mediated by DNA/RNA degeneration. Great efforts have been devoted to unveil the molecular mechanisms behind the OH radical additions to the double bonds of nucleobases; however, the specific role of the biological environment remains relatively unexplored. The present contribution tackles the study of the OH radical addition to uracil from the gas phase to a full RNA macromolecule by means of quantum-chemistry methods combined with molecular dynamics simulations. It is shown that, in addition to the intrinsic reactivity of each position driven by the electronic effects, the presence of bridge water molecules intercalated into the RNA structure favors the addition to the C5 position of uracil in biological conditions. The results also suggest that diffusion of the OH radical does not play a relevant role in the regioselectivity of the reaction, which is mainly controlled at the chemical stage of the addition process

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

Can the Closed-Shell DFT Methods Describe the Thermolysis of 1,2-Dioxetanone?

The chemiluminescent decomposition of 1,2-dioxetanone has in the past been studied by state-of-the-art multireference quantum chemical calculations, and a stepwise biradical mechanism was established. Recently, this decomposition has been reinvestigated, and a concerted mechanism has been proposed based on calculations performed at the closed-shell density functional theory (DFT) level of theory. In order to solve this apparent mechanistic contradiction, the present paper presents restricted and unrestricted DFT results obtained using functionals including different amounts of Hartree–Fock (HF) exchange, repeating and complementing the above-mentioned DFT calculations. The calculated results clearly indicate that the closed-shell DFT methods cannot correctly describe the thermolysis of 1,2-dioxetanone. It is found that unrestricted Kohn–Sham reaction energies and barriers are always lower than the ones obtained using a restricted formalism. Hence, from energy principles, the biradical mechanism is found to be prevailing in the understanding of the 1,2-dioxetanone thermolysis

Chemiluminescence of Coelenterazine and Fluorescence of Coelenteramide: A Systematic Theoretical Study

A systematic investigation of the structural and spectroscopic properties of coelenteramide has been performed at the TD-CAM-B3LYP/6-31+G­(d,p) level of theory, including various fluorescence and chemiluminescence states. The influence of geometric conformations, solvent polarity, protonation state, and the covalent character of the O–H bond of the hydroxyphenyl moiety were carefully studied. Striking differences in geometries and electronic structures among the states responsible for light emission were characterized. All fluorescence states can be described as a limited charge transfer process for a planar amide moiety. However, the chemiluminescence state is characterized by a much larger charge transfer that takes place over a longer distance. Moreover, the chemiluminescent coelenteramide structure exhibits an amide moiety that is no longer planar, in agreement with recent, more accurate <i>ab initio</i> results [Roca-Sanjuán et al. <i>J. Chem. Theory Comput.</i> <b>2011</b>, <i>7</i>, 4060]. Because the chemiluminescence state appears to be completely dark, a new mechanism is tentatively introduced for this process

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