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Excited State Relaxation of Neutral and Basic 8-Oxoguanine Zhen Lu, Ashley A. Beckstead, Bern Kohler, and Spiridoula Matsika J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.5b03565 • Publication Date (Web): 08 Jun 2015 Downloaded from http://pubs.acs.org on June 12, 2015

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The Journal of Physical Chemistry

Excited State Relaxation of Neutral and Basic 8-Oxoguanine Zhen Lu,† Ashley A. Beckstead,‡ Bern Kohler,‡ and Spiridoula Matsika∗,† Department of Chemistry, Temple University, Philadelphia, PA, and Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT E-mail: [email protected]

Abstract 8-Oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dGuo) is one of the most common forms of DNA oxidative damage. Recent studies have shown that 8-oxo-dGuo can repair cyclobutane pyrimidine dimers in double stranded DNA when photo-excited, making its excited state dynamics of particular interest. The excited state lifetimes of 8-oxo-dGuo and its anion have been previously probed using transient absorption spectroscopy, however, more information is required to understand the decay mechanisms. In this work, excited state potential energy surfaces for the neutral and de-protonated forms of the free base, 8-oxoguanine (8-oxo-G), are explored theoretically using multi-reference methods while the nucleoside was experimentally studied using steady-state fluorescence spectroscopy. It is determined that the neutral species exhibits ultra-fast radiationless decay via easy access to conical intersections. The relatively long lifetime for the anion can be explained by the existence of sizable barriers between the FranckCondon region and two S1 /S0 minimum energy conical intersections. A Strickler-Berg analysis of the experimentally measured fluorescence quantum yields and lifetimes is consistent with emission from ππ ∗ excited states in line with theoretical predictions. ∗

To whom correspondence should be addressed Temple University ‡ Montana State University †

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Introduction The damage that occurs when reactive oxygen species and free radicals react with DNA molecules is one of the most prevalent sources of DNA mutation. 8-Oxo-7,8-dihydro-2’deoxyguanosine (8-oxo-dGuo) is the most abundant result of oxidative DNA damage found in humans. 1 The substitution of 8-oxo-dGuo in place of guanine (G) can result in a Hoogsteen base pair with adenine, which may create G to T (thymine) transversion mutations as subsequent replications occur. It has been well established that, under conditions of neutral pH, the dominant tautomer of 8-oxo-dGuo is the 6,8 diketo form. 2 At higher pH, the first deprotonation occurs at the N1 position, resulting in the 6-enolate, 8-keto tautomer, 3 which we refer to as the anion or basic species (8-oxo-dGuo− ). The structures of the nucleosides and corresponding free bases are shown in Figure 1.

(a)

(b)

Figure 1: Structures of (a) neutral 8-oxo-G (free base) for R=H and 8-oxo-dGuo (nucleoside) for R=ribose; b) basic 8-oxo-G− for R=H and 8-oxo-dGuo− for R=ribose. Flavin-based photolyases are a class of DNA repair enzymes responsible for the photoinduced repair of cyclobutane pyridimidine dimers (CPDs) in many species. 4 The flavin mediated repair process involves electron transfer from an excited state of a flavin cofactor, located on photolyase, initiating cleavage of the dimer. In the RNA world hypothesis, it is thought that, previous to the evolution of sophisticated catalysts such as photolyase, many reactions were instead catalyzed by RNA. 5 However, none of the RNA bases seem to be 2


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thermodynamically suited to the specific task of redox catalysis due to the high reduction potentials of their one-electron oxidized forms; the radical of Guo has the lowest reduction potential of all the bases with a mid-point potential of 1.29 V at pH 7, 6 which is still too high. 8-oxo-dGuo has a much smaller potential (0.74 V at pH 7 and 0.5 V at pH 9), 7 making it a more likely candidate for redox catalysis. Furthermore, it was likely to be readily available in the environment of early earth. 8 It has recently been demonstrated that 8-oxo-dGuo can repair CPDs in double stranded DNA, supporting the hypothesis that 8-oxo-G may have been an early precursor to flavin-based photolyases. 9,10 The proposed mechanism for CPD repair involving 8-oxo-dGuo is analogous to that of a flavin-containing photolyase which involves initial excitation followed by electron transfer. Recent studies have confirmed that, when 8-oxo-dGuo is placed in an adenine dinucleotide mimic of FADH2 , the dinucleotide can form radical ion pairs, which is the first step in the repair process. 11 In light of the importance of the excited states of 8-oxo-dGuo in the electron transfer, more detailed information of their behavior including other decay pathways is needed. As the ribose sugar in 8-oxo-dGuo makes it considerably larger, we study theoretically the free base, 8-oxo-G. The excited state lifetimes of the neutral and basic species of the nucleoside have been previously measured with transient absorption spectroscopy. 12 When the excited states of the neutral species are populated via excitation by a UV photon, the population exhibits ultrafast decay on a timescale of 0.9 ± 0.1 ps. As this lifetime is comparable to that of G, which has an excited state lifetime of 0.8 ps, it was suggested that 8-oxo-dGuo likely follows the same dynamics by relaxation via easy access to a conical intersection. 13–16 A very recent study, which includes fluorescence spectra and quantum chemical studies, confirmed the existence of conical intersections in the neutral species similar to the ones in guanine. 17 Unlike the neutral species, the basic species 8-oxo-dGuo− exhibits a much longer S1 excited state lifetime of 43 ± 3 ps, 12 which is almost 50 times greater than that of the neutral species. It is possible that the molecule ejects an electron to become a radical following excitation, but our previous calculations of the vertical detachment energy imply that this is is not energetically feasible. 12 The long excited state lifetime was previously suggested to arise from trapping on a long lived nπ ∗ dark state although a detailed computational analysis to support this claim had not been performed. The current work will revise this proposed mechanism. In order to understand the decay pathways in these systems, further analysis is needed. In this work, we aim to outline the differences in the decay pathways between the neutral and basic free bases in order to understand the large discrepancy in the experimental excited state lifetimes. To this end, we report results from a series of theoretical calculations on the 3



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free bases (8-oxo-G and 8-oxo-G− ) complemented by fluorescence spectra of the nucleosides (8-oxo-dGuo and 8-oxo-dGuo− ). We assume that the main features in the excited state dynamics of 8-oxo-dGuo nucleosides originate in the bases. This assumption for 8-oxo-dGuo is supported by recent studies which show that indeed the base dominates the dynamics. 17 Furthermore, previous studies suggest that the lifetimes of ππ ∗ states are not affected much by the addition of the sugar. 18 Recent work has shown differences between the excited state lifetime of the free base adenine and its nucleoside adenosine, 19 which have been explained using a proton-coupled electron transfer (PCET) deactivation mechanism involving the N3 of the adenine residue and the hydrogen of the 5′ hydroxyl of the ribose group. 20 Even if this ultrafast mechanism is present, it is not expected to contribute greatly to the main difference between neutral and anion 8-oxo-dGuo, which is the long-lived excited state of the anion. Critical points on the S1 excited state potential energy surfaces (PESs) for both the neutral and the anion are found and used to interpret the excited state dynamics and observed fluorescence. Solvation effects are also considered using both implicit and explicit solvation methods to analyze their effects on the excited state surfaces. Finally, a Strickler-Berg analysis of the fluorescence spectra is presented and compared with the theoretical results.

Computational Methods Ground state minimum geometries were optimized at the MP2 level. The cc-pVDZ basis set is used in all calculations reported here. Critical geometries on the potential energy surfaces of both molecules are optimized using the Multi-Reference Configuration Interaction method (MRCI), where only single excitations to the virtual space are included (MRCIS). MRCI is a variational, multireference method that treats well distorted geometries and conical intersections. The MRCIS for the neutral 8-oxo-G molecule uses orbitals from a Complete Active Space Self-Consistent Field (CASSCF) calculation with an active space of 14 electrons in 10 orbitals (14,10) and averages 7 electronic states. The same active space is used in the MRCIS reference space. 7 states were included to ensure stability of the active space through geometry distortions. The (14,10) CAS includes one carbonyl lone pair located on the 6membered ring, one N3 lone pair, and 8 π orbitals. The CAS was chosen as it was the smallest set of orbitals that could qualitatively describe the section of the potential energy surface between the Franck-Condon (FC) region and the conical intersection. Critical geometries for the 8-oxo-G anion were optimized at the MRCIS level using orbitals from a (12,9) CASSCF with 5 states averaged. The (12,9) CAS included one carbonyl lone pair located on the 6membered ring, one N1 lone pair, and 7 π orbitals. A smaller active space is possible for the anion as less mixing occurs when the geometry is distorted away from the FC region. Using 4


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a larger (14,10) active space results in problems with active space stability across geometry distortions. Furthermore, the difference in vertical excitation energies using a (14,10) and (12,9) active space for the anion is minimal (0.1 eV). Linear interpolation paths were created between critical geometries for both the neutral and charged 8-oxo-G species by performing single point calculations at the same level as their respective optimizations. In order to refine the qualitative picture derived from the MRCI energies, the energies are recalculated at the XMCQDPT (eXtended Multi-Configurational Quasi-Degenerate Perturbation Theory) level using optimized MRCI geometries. XMCQDPT has been used previously to yield energies that are in excellent agreement with experiment for small biological systems. 21–23 The active spaces in the XMCQDPT calculations are the same as those used in our MRCI calculations. Since the experimental transient absorption and fluorescence results are conducted in the condensed phase with either H2 O or D2 O solvent, we examine solvent effects in the excited states using several different approaches. Implicit solvation effects were included using the Polarizable Continuum Model (PCM) in combination with CASSCF and XMCQDPT. These calculations were performed at critical geometries for both species using the same active spaces and state averaging as was used for the non-solvated geometries. Limited explicit solvent calculations were included in the anion. One water molecule was placed at important sites of the molecule and optimized at the MP2 level, and the excitation energies were calculated at the CASSCF level as described above. All MRCI single point calculations and optimizations were performed using the COLUMBUS ab initio package. 24–32 XMCQDPT calculations were performed using the Firefly computational chemistry package. 33 CASSCF calculations were performed using the The General Atomic and Molecular Electronic Structure System (GAMESS) computational chemistry package. 34,35 The resulting orbitals were visualized using either MOLDEN 36 or MacMolPlt. 37

Experimental Methods Materials. 8-oxo-dGuo and 2’-deoxyguanosine-5’-monophosphate (dGMP) were obtained from Berry & Associates and Sigma-Aldrich, respectively. All compounds were used as received and solutions were prepared by dissolving solutes in deionized water generated from a filter-based purifier (Synergy, Millipore). Neutral and basic solutions were adjusted to pH 3.0 and pH 10.5 using a few drops of dilute DCl or NaOD, respectively. Deuterated compounds were used because control experiments showed these materials have very low background fluorescence. The quantities of deuterated compounds used were much too small to result in significant H-D exchange of the solute. 5



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Steady-State Spectroscopy. Fluorescence emission spectra were recorded in a 90◦ geometry with 280 nm excitation using a commercial fluorometer (Fluorolog, Jobin Yvon Horiba). All solutions were held in 1 cm path length optical cuvettes with four clear windows. The fluorescence was detected using a photomultiplier tube (PMT). The PMT signal was recorded every 2.5 nm using 5.0 nm slit widths and a 20.0 s integration time. A background scan recorded with neat water was subtracted from the raw emission spectra everywhere except in the region of the Raman peak from water. The spectra were then corrected for the instrument response. Absorption spectra were recorded by placing the same cuvettes and solutions used in the emission measurements into a tabletop UV-vis spectrophotometer (Lambda 25, PerkinElmer). All measurements were carried out at room temperature (20 ± 2◦ C). The optical density of each sample was kept low to avoid the re-absorption of fluorescence. Fluorescence quantum yields were computed using the comparative method with dGMP as a reference. In this case, the fluorescence quantum yields recorded on solutions A and B at the same excitation wavelength are related as shown in Equation 1, IA (1 − 10−ODA )n2A φA , = φB IB (1 − 10−ODB )n2B

(1)

where subscripts A and B denote the two solutes of interest, I is the integrated emission intensity, OD is the optical density or absorbance of the solution at the excitation wavelength, and n is the refractive index of the solution under study. For the dilute solutions studied here, the refractive index was assumed to be the same in all cases and equal to the refractive index of the solvent (water). Each emission spectrum was fit to three Gaussians using the Multipeak Fitting Package 2.0 in the Igor Pro program (version 6.34). One Gaussian modeled the Raman peak from water visible at 309 nm, while the other two Gaussians were used to fit the true emission from the solute. The area of these two Gaussians was calculated analytically and used to determine relative quantum yields using Eq. 1. This procedure was followed to minimize interference from the Raman peak and to account for the long-wavelength tail of the emission spectra that was not recorded above 500 nm.

Potential Energy Surfaces of Neutral 8-oxo-G Table 1 shows the vertical excitation energies (energies at S0 min) of the neutral species computed at the MRCIS and XMCQDPT levels. The first two excited states have ππ ∗ character with similar oscillator strengths. Their energies at the XMCQDPT level (4.27 eV for S1 and 5.29 eV for S2 ) compare well with the experimental absorption spectrum at

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Figure 2: Absorption spectra of 8-oxo-dGuo at pH 3.0 (red trace) and pH 10.5 (blue trace). pH 3 shown in Figure 2, where the maxima for the first two peaks are located at 4.23 and 5.04 eV, respectively. At the MRCIS level, the S1 , S2 , and S3 states are of ππ ∗ , nO π ∗ , and ππ ∗ characters, respectively. Since MRCIS includes minimal dynamical correlation, it overestimates the energies of the ππ ∗ by 1 eV, and does not predict the correct ordering after S1 . However, the S1 state has the correct character using MRCIS, so it is expected that this method can qualitatively describe the S1 PES. Since we are primarily interested in the S1 PES and analytic gradients are not available for XMCQDPT, MRCIS is used for the optimizations on the S1 surface while XMCQDPT is used to refine the energies of the final optimized geometries. Table 1: MRCIS and XMCQDPT energies in eV for neutral 8-oxo-G. Oscillator strengths obtained from the zero order density of XMCQODT are reported in parenthesis. Experimental maxima of absorption spectra are reported for comparison. State S0 S1 (ππ ∗ ) S2 (ππ ∗ ) S3 (nπ ∗ )

S0 min

CI01

MRCIS

XMCQDPT

exp

0.00 5.19 6.12 5.68

0.00 4.27 (0.1447) 5.29 (0.0995) 5.55 (0.0118)

4.23 5.04

MRCIS

XMCQPDT

3.35 3.35

2.95 3.65

Optimized critical geometries for the neutral molecule can be found in Figure 3. We were not able to locate a true minimum on the S1 ππ ∗ excited state surface. Instead an optimization calculation leads directly to a conical intersection seam (CI01 ) between S0 and S1 , with minimum energy 3.35 eV relative to the ground state minimum. Another minimum energy conical intersection was also optimized that may be a local minimum on the same seam. The energy of this conical intersection is 3.66 eV relative to the ground 7



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state minimum. This intersection is very similar to the one recently reported in 8-oxodGuo using TDDFT/PCM methods. 17 The two major distortions required to access either CI are the pyramidalization of C2 and the out of plane motion of the amine group. The conical intersection found in guanine is accessed by very similar distortions. Two conical intersections were recently found in hypoxanthine that share very similar traits to the two reported here. 38 Similarly, the major difference between the two CI geometries reported here is the extent of the out of plane motion of the amine. The C2 -N8 -C3 -N12 dihedral angles are -177o , 158o , and 99o for the ground state minimum, first CI, and second CI, respectively. In the previous work, the less distorted CI was labelled ethylenic II while the more distorted CI was labelled ethylenic I; we shall retain these labels in this work. These CIs are similar and both can be accessed barrierless from the FC region. Since the ethylenic II intersection is both lower in energy and less distorted than the ethylenic I intersection we will give details for this in the following discussion. More details for the ethylenic I CI can be found in Supporting Information (SI, see Figure S1 and related discussion). Future reference to CI01 will refer to the ethylenic II conical intersection. Single point excitation energies at the XMCQDPT level at CI01 are given in Table 1. Since the geometry was optimized at the MRCIS level, we do not expect the energies calculated with XMCQDPT to be degenerate. We therefore estimate the effective energy of the CI as the average energy (3.3 eV) between S1 and S0 . The splitting of the two energies is 0.7 eV, which indicates that correlation will affect both the energy and the location of the CI at the XMCQDPT level. Figure 4 shows linear interpolation pathways connecting the ground state minimum geometry with the ethylenic II CI01 geometry. A similar figure showing the linear interpolation pathway between the S0 minimum geometry and ethylenic I CI01 geometry can be found in Figure S1. The S1 surface is fairly featureless and is very steep between the S0 minimum and each CI at the MRCIS level. This situation is similar to that of the S1 state in guanine, which has been found to also have an essentially barrierless relaxation pathway. 39,40 In the past, researchers have assessed the accessibility of conical intersections in ring systems by using a simple slope approximation where the ”rise” is given by the difference in energy between the Franck-Condon S1 and CI energies and the ”run” is given by the Cremer-Pople puckering parameter. 41 42 Similarly, we have calculated the puckering parameter for the six-membered ring where the bulk of the geometric distortion occurs. The slopes are calculated using the energy difference between the FC region and the CI (∆EF C−CI in eV) divided by the puckering parameter (Q in units of ˚ A) and are given in Table 2. The previously reported values for guanine are also given for comparison. Judging by slope alone, the excited state lifetimes for guanine and neutral 8-oxo-G should be similar and this is consistent with experimental 9




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Table 3: XMCQDPT energies in eV obtained at critical geometries for 8-oxo-G− . Oscillator strengths obtained from the zero order density of XMCQDPT are reported in parenthesis. a Experimental maxima of absorption spectra are reported for comparison. State S0 S1 (ππ ∗ ) S2 (nπ ∗ ) S3 (ππ ∗ )

S0 min 0.00 4.84 (0.0902) 5.41 (0.0002) 5.45 (0.2782)

S1,f old min 4.43

a

5.02a

1.55 4.37 (0.1010) 5.32 (0.0148) 6.10 (0.0063)

S1,twist min

CI01,f old 4.32 4.79 7.13 7.30

2.84 4.08 (0.0186) 5.84 (0.0110) 6.08 (0.0069)

T Stwist

CI01,twist

3.01 4.31 6.00 6.55

3.60 4.30 5.66 6.74

(a) S0 min

(b) S1,f old

(c) CI01,f old fold

(d) S1,twist min

(e) T Stwist

(f) CI01,twist

(g) CI01,f old side view

(h) CI01,twist side view

Figure 5: Geometries for 8-oxo-G− a) Minimum energy geometry for the ground state surface optimized at the MP2/cc-pVDZ level. b-e) Critical geometries on the S1 ππ ∗ surface optimized at the MRCIS/cc-pVDZ level. Bond lengths are given in ˚ A.

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Figure 6: Excited state energies at the MRCIS level along four connected linear interpolation paths between critical points on the S1 ππ ∗ potential energy surface for 8-oxo-G− . strength. Though the XMCQDPT energies compare with experiment more favorably than the MRCIS energies, the error (0.4 eV) is larger than what was seen for the neutral species (0.04 − 0.25 eV). Several critical points on the anion excited state PES were optimized at the MRCIS level. Two minimum energy conical intersection points between the S1 ππ ∗ excited state and ground state were located. The geometries are shown in Figure 5. One of the CIs is very similar to the ethylenic I CI found for the neutral, marked by a large out of plane distortion in the amine group in addition to a distortion in the six membered ring. The other CI is quite different, involving a folding of the molecule about the C4 -C5 bond as well as the pyrimidine ring adopting a boat-like conformation and slight twisting of the imidazole ring. In order to distinguish the two CIs, the former will be denoted as the twist conical intersection CI01,twist , while the latter will be denoted as the fold conical intersection, CI01,f old . The energy of CI01,twist is 4.24 eV at the MRCIS level, while the average of S0 and S1 at this geometry at the XMCQDPT level is 3.95 eV. The energy of CI01,f old is 4.75 eV at the MRCIS level and 4.55 eV at the XMCQDPT level, so this CI is about 0.5 eV higher than CI01,twist . CI01,f old is similar to a CI that was found in xanthine. 43 The FC region is connected to these two CIs through pathways as shown in Figure 6. The intermediate geometries are illustrated in Figure 5 and their excited state energies in Table 3. Figure 6 connects the various geometries with linear interpolation pathways at the MRCIS level. Minimization of S1 starting from the FC region leads to a minimum, denoted here as S1,twist because of its similar distortions compared to CI01,twist . The gap between S1 and S0 at this point is already quite small, 1.24 eV, indicating its proximity to CI01,twist . A transition state has been found which creates a barrier of 0.23 eV between S1,twist and CI01,twist . The transition state has an imaginary frequency of 420 cm−1 , highlighting the 12


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flatness of the surface. The main distortion between the FC region and S1,twist is distortion of the six-membered ring folding in a butterfly motion characterized by the dihedral angle N1 -C2 -N3 -C4 which goes from 1o to 62o . The motion between S1,twist and CI01,twist changes and involves motion of the amino group out of the plane while the N1 -C2 -N3 -C4 remains around 60o . The dihedral angle C4 -N3 -C2 -N2 characterizing the amino out of plane motion changes from 176o at the S0 min to 155o at S1,twist , to 114o at T Stwist and finally to 82o at CI01,twist . One may point out that Figure 6 is misleading in depicting the motion as consisting of a single nuclear motion since the main coordinates change along the way. A different minimum on the S1 PES was also located with distortions similar to CI01,f old . This minimum is actually lower in energy than the conical intersection minimum, creating a natural barrier of 0.4 eV. Geometries and energies for the fold pathway can also be found in Figure 5 and Table 3, respectively. Calculating the energies for the Franck-Condon region, S1 minima, the transition state, and the conical intersection geometries at the XMCQDPT level does not change the qualitative picture of either decay path. Similar to what occurred for the neutral conical intersection, the XMCQDPT conical intersection energies split by 0.5 − 0.7 eV. The energy of the transition state and both S1 minima experience very small changes. Assignments for the states involved in each pathway were done using XMCQDPT transition dipole moments and MRCIS natural orbitals. The character of the S1 state at the S1,f old minimum is very similar to the S1 state in the FC region, while the character at the S1,twist minimum is rather mixed. The transition dipole moments shown in SI (Figure S4) demonstrate this more clearly. This indicates that even though S1,twist is lower in energy, the S1,f old may be reached easier from the FC region. The main relevant feature for the photophysics is that, unlike the neutral species, the anion has a S1 surface that contains barriers that hinder access to conical intersections with the ground state surface. The twist pathway requires 0.23 eV activation energy to overcome the transition state barrier, while the fold pathway has a minimum that is about 0.4 eV below the minimum energy conical intersection. The absence of an easily accessible conical intersection and the presence of barriers on the S1 surface will cause the lifetime of the anion to be much longer than the lifetime of the neutral, for which we have not found any barriers.

Solvation Effects For a more realistic picture, solvation effects have also been calculated for the excited states. In particular, we are interested in how solvation affects accessibility to the CIs, and spectroscopic properties. 13



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Table 4: Energies in eV of excited states for neutral 8-oxo-G obtained at the XMCQDPT level and XMCQDPT+PCM XMCQDPT(+PCM) State S0 S1 (ππ ∗ ) S2 (ππ ∗ )

S0 min 0.00(0.00) 4.27(4.39) 5.29(5.42)

CI01 2.93(2.87) 3.62(3.83) 6.32(6.39)

For the neutral system we use the PCM method in conjunction with CASSCF and XMCQDPT. The XMCQDPT+PCM excitation energies for the neutral species can be found in Table 4. The vertical excitation energies are both blue-shifted by about 0.12 − 0.13 eV, while the energy of CI01 is also blue-shifted by 0.17 eV. The net effect is minimal on the slope towards the CI (seen Table 2) which shifts from 1.51 eV/˚ A to 1.62 eV/˚ A. The small values of the shifts are expected, as both S1 and S2 are of ππ ∗ character and their stabilization in aqueous solution is expected to be similar to that of the ground state. The electronic density of the anion is expected to be diffuse, making the application of the PCM model unreliable. For this reason we have only tested how the excitation energies are affected by the presence of one water molecule at different positions. Details of these calculations are given in SI. The state of major concern in the photophysics is the S1 state. Our calculations predict that explicit solvation blue-shifts the ππ ∗ state by 0.1 − 0.2 eV. Although, we only calculated the shift for vertical excitations it is likely that this shift will be similar across the potential energy surface since the state remains ππ ∗ . On the other hand solvation effects appreciably blue-shift the nπ ∗ state (> 0.5 eV). It is therefore unlikely that the nπ ∗ participates in the decay pathway. Although a more quantitative picture of the dynamics in solution should include explicit calculations along the paths, we believe the current results point to a small effect of solvation.

Fluorescence spectra and interpretation Table 5: Wavelength of maximum fluorescence (λmax ) and fluorescence quantum yields (φf ) f of the compounds studied. φf x104

λmax (nm) f

Species dGMP 8-oxo-dGuo, pH 3.0 8-oxo-dGuo− , pH 10.5

342 350 350 14

1.09 ± 0.10 2.9 ± 0.4 37 ± 6


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with recent experimental observations by Changenet-Barret et al. 17 Whereas the authors of ref. 17 report a quantum yield of (2.3 ± 0.1) × 10−4 for neutral 8-oxo-dGuo, we measure a somewhat higher value of (2.9 ± 0.4) × 10−4 . Overall, our emission spectrum for neutral 8-oxo-dGuo is similar in appearance to the one in ref. 17 with maximum emission close to 350 nm. 8-oxo-dGuo− is considerably more fluorescent than the neutral form as seen in Figure 7a. The increased emission is roughly commensurate with the increased excited state lifetime of the anionic form consistent with emission from a ππ ∗ excited state as discussed below. The emission behavior is also rationalized by the current calculations. The neutral PES of 8-oxo-G is very steep leading to CIs, so emission is expected to be very weak, in agreement with the emission of 8-oxo-dGuo shown in Figure 7. Recent work using TDDFT on 8-oxodGuo, which found a similar CI to ours, suggested that the emission observed may be from a plateau on the PES. 17 Furthermore, the similarities of the TDDFT study to ours are a good indicator that studying the free base is sufficient. Contrary to 8-oxo-G, the barriers we found on the anion 8-oxo-G− S1 PES inhibit easy access to conical intersections, and fluorescence is expected to be more pronounced. In a previous work we had hypothesized that the long lived anionic excited state could be attributed to population trapping on a dark nπ ∗ state. Since the ππ ∗ and nπ ∗ states are fairly closely spaced at vertical excitation for the anion, it is possible that there could exist a pathway that allows the bright ππ ∗ state to cross with a dark nπ ∗ state, resulting in population trapping. However, we have only found pathways where ππ ∗ states play a role. To this end, we looked for additional pathways including the nπ ∗ state. A conical intersection between the nπ ∗ state and the ππ ∗ state exists, but it is 0.5 eV higher than the vertical excitation of the S1 state, and thus inaccessible (see more details in SI). In addition, solvation will shift the nπ ∗ to much higher energies, making it even less accessible in aqueous solution. The steady-state fluorescence spectra recorded in Figure 7, however, seem to justify the alternative explanation given in this work, which is that ππ ∗ states contribute to the long excited state lifetime. The strong emission from 8-oxo-dGuo− found in our fluorescence spectra is consistent with a bright ππ ∗ state and not a dark state. Emission from a bright ππ ∗ state is further supported by a Strickler-Berg analysis. 45 The experimental lifetimes of 8-oxo-dGuo− and 8-oxo-dGuo are 43 ps and 0.9 ps, 12 respectively, corresponding to a ratio of 48. The radiative lifetime of each form of 8-oxo-dGuo was estimated from the StricklerBerg equation by integrating the longest wavelength band in the experimental absorption spectrum. From these values and the fluorescence quantum yields in Table 5, the ratio of the fluorescence lifetime of 8-oxo-dGuo− to that of 8-oxo-dGuo is predicted to be 16. However, when the radiative lifetime of the neutral form of 8-oxo-dGuo is calculated from the StricklerBerg equation using the two longest wavelength absorption bands, the lifetime ratio is found 16


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to be 40 in much better agreement with the measured value of 48. Earlier, Cohen et al. 45 used the Strickler-Berg equation to calculate radiative lifetimes for five common nucleosides from experimental absorption spectra. They showed that fluorescence lifetimes calculated as the product of the predicted radiative lifetime and the experimental fluorescence quantum yield are in much better agreement with the experimental lifetimes of the purine nucleosides adenosine and guanosine when both lowest ππ ∗ transitions are included in the Strickler-Berg equation. This non-Kasha behavior, which suggests that both ππ ∗ transitions contribute to the emission, is expected when the excited-state lifetime is comparable to the time needed for internal conversion between singlet states. This is proposed to be the case here for the neutral form of 8-oxo-dGuo, but not for the longer-lived 8-oxo-dGuo− . Like other short-lived purine nucleosides, 45 the neutral form of 8-oxo-dGuo may thus be emissive from both lowest ππ ∗ excited states even though the energetic separation between these two states is greater for 8-oxo-dGuo than for adenosine and guanosine. The fluorescence maximum of the anion occurs at 350 nm, which corresponds to a 3.54 eV gap between the S1 state and the ground state at the excited state minimum geometry. As shown in Table 3, the S1 -S0 gap at the S1 min for the twist pathway is 1.34 eV, which is much smaller than the fluorescence maximum. However, the gap for the fold pathway is 2.82 eV, which is in better agreement with the experimental spectrum. The oscillator strength is much higher for S1,f old too (f = 0.1, see Table 3), suggesting that this is the fluorescent minimum. This leads us to believe that the fold pathway dominates the excited state fluorescence for the anion. Figure 8 gives a summary of our current understanding of the dynamics of 8-oxo-G− . Upon excitation, the S1 state is populated either directly or by radiationless decay from the higher excited states. Two unique pathways are open to decay back to the ground state. In either case, ultra-fast decay via conical intersection is inhibited by the existence of barriers on the excited state surface. Our fluorescence spectrum is best explained by emission that is dominated by the S1 minimum located on the fold pathway. The energy gap for the twist minimum is small and the oscillator strength and transition dipole moment for S1 at the fold minimum is also much higher than at the twist minimum.

Conclusions Excitation of neutral 8-oxo-G in the gas phase results in ultrafast decay via a barrierless descent to S1 /S0 conical intersections. Analysis of the accessibility of the conical intersections using the energy difference between the Franck-Condon region and the conical intersection divided by the Cremer-Pople Puckering Parameter supports this finding as ∆ EF C−CI /Q for 17



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Figure 8: Summary of the excited state behavior for 8-oxo-G− guanine and 8-oxo-G are very similar. Two unique decay pathways were outlined for the anion which we label the fold and the twist pathways. The long lived excited state in 8-oxo-G− can be explained by appreciable barriers of 0.2 - 0.4 eV on the S1 excited state surface in either pathway, inhibiting easy access to the conical intersections. It is likely that emission occurs from the S1 minimum along the fold pathway, as this is consistent with the observed fluorescence spectrum. It should be clarified here that our conclusions are based on PESs and minimum energy paths. Although PESs provide good insight into the excited state dynamics of molecules, reliable molecular dynamics calculations are needed for a more complete picture of the dynamics.. Fluorescence studies and Strickler-Berg analysis on 8-oxo-dGuo support our findings by showing that the anion emits much more strongly than the neutral species. This strong fluorescence emission is consistent with our explanation that barriers exist on the bright ππ ∗ state PES.

Acknowledgements Support by the National Science Foundation under Grant CHE-1213614 is acknowledged. We would like to thank George Pantelopulos from the Voelz Lab at Temple University for his help with calculations. Work at Montana State University was supported by NASA (NNX12AG77G). 18


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Supporting Information Available Further information regarding the alternative conical intersection in the neutral molecule as well as solvation effects on the anion can be found in the supporting information. This information is available free of charge via the Internet at http://pubs.acs.org.

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