DNA Photodamage and Repair: Computational Photobiology in Action

Francés‐Monerris, Antonio; Gillet, Natacha; Dumont, Élise; Monari, Antonio

doi:10.1007/978-3-030-57721-6_7

Cited by 3 publications

(12 citation statements)

References 243 publications

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“…Thymine plays a central role in DNA photochemistry. Indeed, direct absorption of UV-light leads to thymine dimerization, producing either cyclobutane pyrimidine dimers (CPD) or 6-4 photoproduct (64-PP) as the most common lesions (1)(2)(3). The former damages are also toxic when they accumulate, as they are either repair-resistant or highly mutagenic and are correlated to the development of malignant skin cancers as the result of unprotected exposure to sunlight (4)(5)(6)(7).…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, its triplet state, the lowest among the natural nucleobases, can be populated via triplet-triplet energy transfer from the excited sensitizer. This process can also be facilitated by the additional stabilization of thymine triplet 3 T due to π-stacking, and the related multichromophoric coupling in the DNA helical structure. Thymine photochemistry has been explored as early as 1960s (11), but the presence of 3 T (12) has triggered renewed attention, notably for delineating the mechanism of triplet-triplet energy transfer with external photosensitizers (13), or with modified nucleobases and oxidative lesions recognized as Trojan Horses (9,14).…”

Section: Introductionmentioning

confidence: 99%

“…Thymine photochemistry has been explored as early as 1960s (11), but the presence of 3 T (12) has triggered renewed attention, notably for delineating the mechanism of triplet-triplet energy transfer with external photosensitizers (13), or with modified nucleobases and oxidative lesions recognized as Trojan Horses (9,14). It has also been shown that the population of 3 T opens rather efficient photochemical channels for dimerization (15,16), even if there is no experimental evidences for the formation of 64-PP mediated by 3 T. The energy of 3 T in a DNA strand has been inferred experimentally by Bosca et al by assessing the energy transfer efficiency of different photosensitizers, such as norfloxacin and its N4'-acetyl derivative, whose energies are precisely known (17).…”

Section: Introductionmentioning

confidence: 99%

“…The assumption being that only those sensitizers whose triplet state is higher than the one of 3 T embedded in the DNA environment will be able to induce energy transfer. This approach has provided a reference value of 270 kJ mol −1 , which confirms the stabilization of 3 T in DNA and provides a macroscopic average in a complex environment. Yet this value encompasses a manifold of different nucleobases whose direct surroundings differs largely.…”

Section: Introductionmentioning

confidence: 99%

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The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*

Allahkaram

Monari

Dumont

2021

Photochem & Photobiology

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Among the naturally occurring nucleobases, thymine presents the lowest triplet state, hence it represents a hotspot for energy transfer and photosensitization. In turn, the population of the triplet state may lead to thymine dimerization and hence to the production of toxic DNA lesions and has been the subject of intensive theoretical and experimental investigations. Relying on QM/MM molecular dynamics simulations, we have sought to situate the energy of the lowest triplet state of thymine embedded in a B‐DNA environment. The energy gap varies between 305 and 329 kJ mol−1 when a single thymine is treated at the quantum chemistry level, depending on its position in the model double‐stranded 16‐bp oligonucleotide. The energy of triplet state decreases up to 300 kJ mol−1, due to polarization effects, when we consider coupled stacked nucleobases up to the inclusion of four nucleobases. Our value lies in good agreement with the energy inferred experimentally by Miranda and coworkers (270 kJ mol−1), and our theoretical exploration opens the door to investigations toward other more complex and biologically relevant environments, such as thymines embedded in nucleosome core particles. Our investigations also provide a reference for further studies using semi‐empirical approaches such as density functional‐based tight‐binding, allowing to further rationalize sequence effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*

Allahkaram

Monari

Dumont

2021

Photochem & Photobiology

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“…The direct absorption of ultraviolet light causes the most abundant lesions in DNA, namely cyclobutane pyrimidine dimers (CPD) and (6-4) photoproducts (6-4PP) [ 1 , 2 , 3 ]. The impact of DNA lesions in living beings is mostly mitigated by DNA repair mechanisms that have been shaped throughout evolution.…”

Section: Introductionmentioning

confidence: 99%

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

et al. 2021

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Photocycloreversion plays a central role in the study of the repair of DNA lesions, reverting them into the original pyrimidine nucleobases. Particularly, among the proposed mechanisms for the repair of DNA (6-4) photoproducts by photolyases, it has been suggested that it takes place through an intermediate characterized by a four-membered heterocyclic oxetane or azetidine ring, whose opening requires the reduction of the fused nucleobases. The specific role of this electron transfer step and its impact on the ring opening energetics remain to be understood. These processes are studied herein by means of quantum-chemical calculations on the two azetidine stereoisomers obtained from photocycloaddition between 6-azauracil and cyclohexene. First, we analyze the efficiency of the electron-transfer processes by computing the redox properties of the azetidine isomers as well as those of a series of aromatic photosensitizers acting as photoreductants and photo-oxidants. We find certain stereodifferentiation favoring oxidation of the cis-isomer, in agreement with previous experimental data. Second, we determine the reaction profiles of the ring-opening mechanism of the cationic, neutral, and anionic systems and assess their feasibility based on their energy barrier heights and the stability of the reactants and products. Results show that oxidation largely decreases the ring-opening energy barrier for both stereoisomers, even though the process is forecast as too slow to be competitive. Conversely, one-electron reduction dramatically facilitates the ring opening of the azetidine heterocycle. Considering the overall quantum-chemistry findings, N,N-dimethylaniline is proposed as an efficient photosensitizer to trigger the photoinduced cycloreversion of the DNA lesion model.

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Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

Abdelgawwad

Monari

Tuñón

et al. 2022

J. Chem. Inf. Model.

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DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O 2 . However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson–Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.

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DNA Photodamage and Repair: Computational Photobiology in Action

Cited by 3 publications

References 243 publications

The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*

The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

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DNA Photodamage and Repair: Computational Photobiology in Action

Cited by 3 publications

References 243 publications

The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations†*

The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations†*

Theoretical Study on the Photo-Oxidation and Photoreduction of an Azetidine Derivative as a Model of DNA Repair

Spatial and Temporal Resolution of the Oxygen-Independent Photoinduced DNA Interstrand Cross-Linking by a Nitroimidazole Derivative

Contact Info

Product

Resources

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The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*

The Behavior of Triplet Thymine in a Model B‐DNA Strand. Energetics and Spin Density Localization Revealed by ab initio Molecular Dynamics Simulations^†*