Edinburgh Research Explorer Sequential electron transfer governs the UV-induced self-repair of DNA photolesions Citation for published version: Szabla, R, Kruse, H, Stadlbauer, P, Šponer, J & Sobolewski, AL 2018, 'Sequential electron transfer governs the UV-induced self-repair of DNA photolesions', Chemical Science, vol. 9, no. 12, pp. 3131-3140. https://doi.org/10.1039/c8sc00024g Digital Object Identifier (DOI): 10.1039/c8sc00024g Link: Link to publication record in Edinburgh Research Explorer Document Version: Publisher's PDF, also known as Version of record Published In: Chemical Science General rights Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s) and / or other copyright owners and it is a condition of accessing these publications that users recognise and abide by the legal requirements associated with these rights. Take down policy The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer content complies with UK legislation. If you believe that the public display of this file breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 28. Sep. 2021 Chemical Science View Article Online EDGE ARTICLE View Journal | View Issue Sequential electron transfer governs the UV- induced self-repair of DNA photolesions† Cite this: Chem. Sci.,2018,9,3131 ab b bc b Rafał Szabla, * Holger Kruse, Petr Stadlbauer, Jiˇr´ı Sponerˇ and Andrzej L. Sobolewskia Cyclobutane pyrimidine dimers (CpDs) are among the most common DNA lesions occurring due to the interaction with ultraviolet light. While photolyases have been well known as external factors repairing CpDs, the intrinsic self-repairing capabilities of the GAT]T DNA sequence were discovered only recently and are still largely obscure. Here, we elucidate the mechanistic details of this self-repair process by means of MD simulations and QM/MM computations involving the algebraic diagrammatic construction to the second order [ADC(2)] method. We show that local UV-excitation of guanine may be followed by up to three subsequent electron transfers, which may eventually enable efficient CpD ring opening when the negative charge resides on the T]T dimer. Consequently, the molecular mechanism of GAT]T self- repair can be envisaged as sequential electron transfer (SET) occurring downhill along the slope of the S1 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. potential energy surface. Even though the general features of the SET mechanism are retained in both of the studied stacked conformers, our optimizations of different S1/S0 state crossings revealed minor differences which could influence their self-repair efficiencies. We expect that such assessment of the Received 3rd January 2018 availability and efficiency of the SET process in other DNA oligomers could hint towards other sequences Accepted 22nd February 2018 exhibiting similar photochemical properties. Such explorations will be particularly fascinating in the DOI: 10.1039/c8sc00024g context of the origins of biomolecules on Earth, owing to the lack of external repairing factors in the rsc.li/chemical-science Archean age. This article is licensed under a Introduction formation and repair have been attracting signicant attention involving both experimental and theoretical studies.8–17 Dimerization of DNA bases is one of the most detrimental The vulnerability of DNA and RNA to the harmful effects of Open Access Article. Published on 22 February 2018. Downloaded 12/18/2020 10:02:34 AM. phenomena occurring during the exposure of nucleic acid UV-radiation is particularly intriguing in the context of the strands to UV-light.1 Cyclobutane pyrimidine dimers (CpDs) origins of life. First of all, it is reasonable to assume that the and (6-4) lesions can be classied among the most frequent highly sophisticated photolyases were absent during the emer- photodimers and are responsible for mutagenic processes gence of the rst oligonucleotides. Furthermore, recent theo- driven by hindered transcription and DNA replication.2 To retical estimates showed that much higher amounts of UV-light protect living organisms from such UV-activated stress, nature were reaching the surface of the Archean Earth, owing to the developed sophisticated enzymes, i.e. photolyases, which lack of oxygen in the atmosphere and higher Sun activity in the – selectively repair CpDs and (6-4) lesions via electron transfer or ultraviolet spectral range.18 22 Interestingly, a recent work by proton-coupled electron transfer processes.3,4 Despite the exis- Bucher et al.23 revealed that specic DNA sequences may tence of repairing machinery, DNA photolesions are a common promote very efficient self-repair driven by photoinduced elec- cause of skin cancer1,5–7 and the mechanistic details of their tron transfer to the CpD lesion containing two dimerized thymine bases (T]T). This remarkable property was discovered for the GAT]T sequence in single and double strands, while no 23 aInstitute of Physics, Polish Academy of Sciences, Al. Lotnikow´ 32/46, PL-02668 repair was reported for the TAT]T and AT]T oligomers. The Warsaw, Poland signicant selectivity of this process implies that UV-light bInstitute of Biophysics of the Czech Academy of Sciences, Kralovopolsk´ a´ 135, 61265 played an important role in the prebiotic selection of the Brno, Czech Republic. E-mail: [email protected] most photochemically stable nucleic acid sequences.24 cRegional Centre of Advanced Technologies and Materials, Department of Physical Many fundamental aspects of the photochemistry of nucleic ´ Chemistry, Faculty of Science, Palacky University, 17. Listopadu 1192/12, 77146 ] Olomouc, Czech Republic acid oligomers (such as GAT T) are still obscure, including the † Electronic supplementary information (ESI) available: Computational details of relative contribution of locally-excited (LE) and delocalized the MD simulations, results of calculations performed for the GA-syn conformer, excitations in DNA strands, the extent of the charge-transfer diabatic couplings and Cartesian coordinates of the stationary points. See DOI: (CT) character of the latter, and the availability of different 10.1039/c8sc00024g This journal is © The Royal Society of Chemistry 2018 Chem. Sci.,2018,9,3131–3140 | 3131 View Article Online Chemical Science Edge Article photorelaxation pathways in such assemblies.25,26 While some Computational methods valuable insights into these processes were provided by time- resolved (TR) spectroscopic (e.g. transient absorption UV) MD simulations techniques,27 it is generally difficult to study the clear origin of The initial geometry of the GAT]T tetranucleotide was the long-lived states due to overlapping absorption features of prepared in the B-DNA helical form. The T]T residue was different nucleobases.25 In addition, selective synthesis of prepared in the same way as the standard AMBER nucleotides.40 specic photodamaged sequences is challenging. On the other The torsion parameters for the cyclobutane ring in the T]T hand, considerable system sizes oen restrict the applications dimer given by the standard atomic types of the parmOL15 force of theoretical simulations to methods such as Time-Dependent eld41–44 were found satisfactory according to our test simula- Density Functional Theory (TDDFT). Even though TDDFT was tion. MD simulations were carried out under the parmOL15 employed with some success in investigations of photochemical force eld41–44 in an octahedral box of explicit water molecules and photophysical properties of oligonucleotides,28,29 the (either SPC/E,45 or OPC model46) with 0.15 M excess KCl,47 using applicability of this methodology to similar problems has been the AMBER soware package.48 Each of these simulations was criticized because of oen signicant overstabilization of CT propagated for 10 ms. The trajectories were clustered by states.26,30,31 While range-separated functionals can alleviate this a custom modied algorithm49 of Rodriguez et al.,50 using the problem to some extent for vertical excitations, nonadiabatic eRMSD metric.51 More details about the MD simulations are molecular dynamics simulations of adenine with TDDFT failed included in the ESI† to this article. to correctly describe the excited-state lifetimes and photo- deactivation pathways.32 QM/MM simulations In the light of the above discussion, characterization of photoinduced processes in oligonucleotides based on highly The geometries of selected (GA-anti and GA-syn) conformers accurate quantum-chemical methods is urgently needed. In obtained from the clustering procedure were further utilized in the QM/MM calculations. These geometries were solvated in Creative Commons Attribution-NonCommercial 3.0 Unported Licence. particular, a much more balanced description of the LE and CT – a spherical droplet of SPC/E explicit water molecules, with states, even outside the Franck Condon region, can be obtained ˚ with the algebraic diagrammatic construction to the second a radius of 25 A. The solvent was then equilibrated for 10 ps, in order [ADC(2)] method.33,34 The ADC(2) method was recently order to obtain a reasonable distribution of the water molecules ff proved to provide reliable results in the investigations of the within the sphere. We considered two di erent QM/MM setups: photochemistry of nucleic acids fragments within the QM/MM QMDNA/MM setup contained the whole tetranucleotide treated framework (referred