The photophysics and photochemistry of DNA is of great importance due to the potential damage of the genetic code by UV light. Quantum mechanical studies have played a key role in interpretating the results of modern time-resolved pump-probe spectroscopy, and in elucidating the main photoactivated reactive paths. This review provides a concise, complete picture of the computational studies carried out, approximately, in the past decade. We start with an overview of the photophysics of the nucleobases in the gas phase and in solution. We discuss the proposed mechanisms for ultrafast decay to the ground state, that involve conical intersections, consider the role of triplet states, and analyze how the solvent modulates the photophysics. Then we move to larger systems, from dinucleotides to single- and double-stranded oligonucleotides. We focus on the possible role of charge transfer and delocalized or excitonic states in the photophysics of these systems and discuss the main photochemical paths. We finish with an outlook on the current challenges in the field and future directions of research.

Quantum Mechanical Studies on the Photophysics and the Photochemistry of Nucleic Acids and Nucleobases

Ultraviolet (UV) radiation is a leading external hazard to the integrity of DNA. Exposure to UV radiation triggers a cascade of chemical reactions, and many molecular products (photolesions) have been isolated that are potentially dangerous for the cellular system. The early steps that take place after UV absorption by DNA have been studied by ultrafast spectroscopy. The review focuses on the evolution of excited electronic states, the formation of photolesions, and processes suppressing their formation. Emphasis is placed on lesions involving two thymine bases, such as the cyclobutane pyrimidine dimer, the (6-4) lesion, and its Dewar valence isomer.

Early events of DNA photodamage.

The dynamics responsible for triggering the Photoactive Yellow Protein photocycle have been disentangled with the dispersed ultrafast pump-dump-probe spectroscopy technique, where the photocycle can be started and interrupted with appropriately tuned and timed laser pulses.

Incoherent manipulation of the photoactive yellow protein photocycle with dispersed pump-dump-probe spectroscopy

UV radiation creates excited states in DNA that lead to mutagenic photoproducts. Photoexcitation of single-stranded DNA can transfer an electron between stacked bases, but the fate of excited states in the double helix has been intensely debated. Here, photoinduced interstrand proton transfer (PT) triggered by intrastrand electron transfer (ET) is detected for the first time by time-resolved vibrational spectroscopy and quantum mechanical calculations. Long-lived excited states are shown to be oppositely charged base pair radical ions. In two of the duplexes, the base pair radical anions are present as tautomers formed by interstrand PT. Charge recombination occurs on the picosecond time scale preventing the accumulation of damaging radicals or mutagenic tautomers.

https://pubs.acs.org/doi/pdf/10.1021/jacs.5b03914

UV-Induced Proton Transfer between DNA Strands

Photophysical investigations of the canonical nucleobases that make up DNA and RNA during the past 15 years have revealed that excited states formed by the absorption of UV radiation decay with subpicosecond lifetimes (i.e., <10−12 s). Ultrashort lifetimes are a general property of absorbing sunscreen molecules, suggesting that the nucleobases are molecular survivors of a harsh UV environment. Encoding the genome using photostable building blocks is an elegant solution to the threat of photochemical damage. Ultrafast excited-state deactivation strongly supports the hypothesis that UV radiation played a major role in shaping molecular inventories on the early Earth before the emergence of life and the subsequent development of a protective ozone shield. Here, we review the general physical and chemical principles that underlie the photostability, or “UV hardiness”, of modern nucleic acids and discuss the possible implications of these findings for prebiotic chemical evolution. In RNA and DNA strands, much longer-lived excited states are observed, which at first glance appear to increase the risk of photochemistry. It is proposed that the dramatically different photoproperties that emerge from assemblies of photostable building blocks may explain the transition from a world of molecular survival to a world in which energy-rich excited electronic states were eventually tamed for biological purposes such as energy transduction, signaling, and repair of the genetic machinery.

Life in the light: nucleic acid photoproperties as a legacy of chemical evolution.

During the early evolution of life, 8-oxo-7,8-dihydro-2′-deoxyguanosine (O) may have functioned as a proto-flavin capable of repairing cyclobutane pyrimidine dimers in DNA or RNA by photoinduced electron transfer using longer wavelength UVB radiation. To investigate the ability of O to act as an excited-state electron donor, a dinucleotide mimic of the FADH 2 cofactor containing O at the 5′-end and 2′-deoxyadenosine at the 3′-end was studied by femtosecond transient absorption spectroscopy in aqueous solution. Following excitation with a UV pulse, a broadband mid-IR pulse probed vibrational modes of ground-state and electronically excited molecules in the double-bond stretching region. Global analysis of time- and frequency-resolved transient absorption data coupled with ab initio quantum mechanical calculations reveal vibrational marker bands of nucleobase radical ions formed by electron transfer from O to 2′-deoxyadenosine. The quantum yield of charge separation is 0.4 at 265 nm, but decreases to 0.1 at 295 nm. Charge recombination occurs in 60 ps before the O radical cation can lose a deuteron to water. Kinetic and thermodynamic considerations strongly suggest that all nucleobases can undergo ultrafast charge separation when π-stacked in DNA or RNA. Interbase charge transfer is proposed to be a major decay pathway for UV excited states of nucleic acids of great importance for photostability as well as photoredox activity.

https://www.pnas.org/content/pnas/111/32/11612.full.pdf

Efficient UV-induced charge separation and recombination in an 8-oxoguanine-containing dinucleotide

Femtosecond time-resolved IR spectroscopy is used to investigate the excited-state dynamics of a dinucleotide containing an 8-oxoguanine anion at the 5′-end and neutral adenine at the 3′-end. UV excitation of the dinucleotide transfers an electron from deprotonated 8-oxoguanine to its π-stacked neighbor adenine in less than 1 ps, generating a neutral 8-oxoguanine radical and an adenine radical anion. These species are identified by the excellent agreement between the experimental and calculated IR difference spectra. The quantum efficiency of this ultrafast charge shift reaction approaches unity. Back electron transfer from the adenine radical anion to the 8-oxguanine neutral radical occurs in 9 ps, or approximately 6 times faster than between the adenine radical anion and the 8-oxoguanine radical cation (Zhang, Y. et al. Proc. Natl. Acad. Sci. U.S.A. 2014, 111, 11612–11617). The large asymmetry in forward and back electron transfer rates is fully rationalized by semiclassical nonadiabatic electron transf...

Photoinduced Electron Transfer in DNA: Charge Shift Dynamics between 8-Oxo-Guanine Anion and Adenine

The excited-state dynamics of two cyclic DNA miniduplexes, each containing just two base pairs, are investigated using time-resolved infrared spectroscopy. As in longer DNA duplexes, intrastrand electron transfer induced by UV excitation triggers interstrand proton transfer in the alternating miniduplex containing two out-of-phase G·C base pairs. The resulting excited state decays on a time scale of several tens of picoseconds. This state is absent when one of the two G residues is substituted by 8-oxo-7,8-dihydroguanine, a modification that is suggested to disrupt base stacking, while maintaining base pairing. These findings demonstrate that a nucleobase tetramer arranged as two stacked base pairs accurately captures the interplay between intrastrand and interstrand decay channels. The similar signals seen in the miniduplexes and longer sequences suggest that excited states in the latter rapidly localize on two adjacent base pairs.

UV-Induced Proton-Coupled Electron Transfer in Cyclic DNA Miniduplexes.

Nguyen and Burrows recently demonstrated that UV-B irradiation of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a signature product of oxidatively damaged DNA, can repair cyclobutane pyrimidine dimers in double-stranded DNA (J. Am. Chem. Soc. 2011, 133, 14586−14589). In order to test the hypothesis that repair occurs by photoinduced electron transfer, it is critical to determine basic photophysical parameters of 8-oxodG including the excited-state lifetime. Here, femtosecond transient absorption spectroscopy was used to study the ultrafast excited-state dynamics of 8-oxodG with excitation in the UV and probing at visible and mid-IR wavelengths. The excited-state lifetimes of both neutral and basic forms of 8-oxodG in D2O are reported for the first time by monitoring the disappearance of excited-state absorption at 570 nm. The lifetime of the first excited state of the neutral form is 0.9 ± 0.1 ps, or nearly twice as long as that of 2′-deoxyguanosine. The basic form of 8-oxodG exhibits a much longer excit...

Ultrafast Excited-State Dynamics and Vibrational Cooling of 8-Oxo-7,8-dihydro-2′-deoxyguanosine in D2O

It is known that a context-free grammar (CFG) that produces a single string can be derived from the compact directed acyclic word graph (CDAWG) for the same string. In this work, we show that the CFG derived from a CDAWG is deeply connected to the maximal repeat content of the string it produces and thus has O(m) rules, where m is the number of maximal repeats in the string. We then provide a generic algorithm based on this insight for constructing the CFG from the LCP-intervals of a string in O(n) time, where n is the length of the string. This includes a novel data-structure to support stabbing queries on LCPintervals in O(1+k) time after O(n) preprocessing time, where k is the number of intervals stabbed. These results connect the CFG to properties of the string it produces and relates it to other string data-structures, allowing it to be studied independently of the CDAWG and providing opportunity for innovation of grammar-based compression algorithms.

Jordan Dood

Papers

Efficient UV-induced charge separation and recombination in an 8-oxoguanine-containing dinucleotide

Photoinduced Electron Transfer in DNA: Charge Shift Dynamics between 8-Oxo-Guanine Anion and Adenine

UV-Induced Proton-Coupled Electron Transfer in Cyclic DNA Miniduplexes.

Ultrafast Excited-State Dynamics and Vibrational Cooling of 8-Oxo-7,8-dihydro-2′-deoxyguanosine in D2O

Constructing the CDAWG CFG using LCP-Intervals