How Does the O6-Methylation Regulate the Excited-State Decay of

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B: Liquids, Chemical and Dynamical Processes in Solution, Spectroscopy in Solution 6

How Does the O-Methylation Regulate the Excited-State Decay of Guanine Monomers Panwang Zhou, and Li Zhao J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.8b08606 • Publication Date (Web): 13 Dec 2018 Downloaded from http://pubs.acs.org on December 18, 2018

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The Journal of Physical Chemistry

How Does the O6-Methylation Regulate the ExcitedState Decay of Guanine Monomers Panwang Zhou,a* Li Zhaob aState

Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian 116023, Liaoning, China

bSchool

of Science, China University of Petroleum, Qingdao 266580, Shandong, China Email: [email protected] Phone: +8641184379195

ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Abstract In this study, the photoinduced ultrafast deactivations of O6-methylguanosine in aqueous solution are mapped by employing multireference methods with implicit solvation model on a reduced model compound 9-methyl-O6-methylguanine (9Me6MeGua). Although four S1/S0 minimal energy conical intersections (MECIs) are located, energy profiles indicated that only two of them are involved in excited-state decay processes and account for the C2 and C6 reaction coordinates, respectively. To reach both the involved MECIs, 9Me-6MeGua need to surmount an energy barrier. The computed energy barrier of C6 reaction coordinate is extremely low and should be responsible for the experimentally observed fast internal conversion (IC) process (~0.95 ps), whereas the C2 reaction coordinate accounts for the slow IC process (~41 ps). Eventually, we deliver a detailed mechanism for ultrafast deactivations of 6MeGuo, which explains well the recent experimental results (J. Phys. Chem. Lett. 2017, 8, 43804385) and revises the proposed mechanism.


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Introduction An increasing number of experimental and theoretical studies1-9 have been conducted to investigate the excited-state dynamics of methylated DNA bases because they are relevant for photostability and photodamage of DNA upon UV irradiation. The most prevalent methylated DNA base is 5-methylated cytosine (5mCyt), which is correlated with the formation of cyclobutene pyrimidine dimers (CPDs) and plays a vital role in UV-induced carcinogenesis as the mutational hotspot.10-14 The photophysical and photochemical mechanisms of 5mCyt and its derivatives in gas phase and in different solvents have been studied in detail.1-5 The proposed excited-state deactivation mechanisms show that the C5-methylation of cytosine bases will remarkably increase the excited state lifetime, thereby accelerating DNA photodamage.1-5 Another important methylated adduct in DAN is O6-methylguanosine (6MeGuo), which is generated from alkylation of the O6 position of guanosine by alkylating agents, such as N-nitroso compounds15 and endogenous S-adenosyl methionine.16 6MeGuo bears high mutagenic and carcinogenic potential, primarily due to its mispairing with the thymine base during DNA replication, therefore inducing guanine-cytosine (GC) to adenine-thymine (AT) conversion mutations.17-21 Furthermore, O6-methylation significantly alters the excited-state dynamics and photochemistry of guanine (Gua) monomers.7 Recently, by employing broadband femtosecond transient absorption spectroscopy, Ashwood and co-workers found that the first excited-state (S1) of 6MeGuo in aqueous solution decay to the ground state (S0) through two parallel pathways.7 The first pathway involves C2 puckering and pyramidalization of the amino group (C2 reaction coordinate) with a lifetime about 1 ps, and the second pathway involves bending of O6-methyl group and pyramidalization of the C6 atom (C6 reaction coordinate) with a lifetime about 40 ps.7 Because the ~1 ps decay has also been



observed for Gua monomers in aqueous solution,22-25 Ashwood and co-workers proposed that the C6 reaction coordinate is the primary relaxation pathway of 6MeGuo and corresponding to the slow decay.7 However, there is no direct evidence support this suggestion. The structures of the involved minimal energy conical intersections (MECIs) and their relative energies remain unknown. Moreover, transition state should exist for the slow decay process (~40 ps) and it is necessary to determine its geometry and energy. Therefore, in this letter, we conducted a theoretical study to investigate the relaxation dynamics of 6MeGuo in aqueous solution with the multireference methods. The potential energy surfaces (PES) along the C2 and C6 reaction coordinates of 6MeGuo are constructed and the detailed excited-state decay mechanisms are provided. Importantly, our theoretical results revealed that the slow decay process of 6MeGuo should result from the C2 reaction coordinate, but not the proposed C6 reaction coordinate by Ashwood and co-workers.7 Results and discussion To reduce the computational cost, the ribose of 6MeGuo was replaced with methyl group and the model compound 9-methyl-O6-methylguanine (9Me-6MeGua, Figure 1) was used in our calculations. Previous study has demonstrated that this reduced model should be reasonable.23 Moreover, the experimental and theoretical results on 6MeGuo7 and guanosine monophosphate (GMP)23 shown that the excited-state decay of Gua Monomers only involve the first excited state (ππ*, La). Therefore, only two states are included in our complete-active-space self-consistent-field (CASSCF) calculations and the active space comprises 10π electrons in 9π orbitals (see Figure S1). Figure 1 shows the optimized ground (S0-min) and first excited-state (S1-min) geometries of 9Me-6MeGua in aqueous solution with the equal-weight two-root (S0, S1) state-average (SA2) CASSCF method. The 6-31G(d) basis set was adopted and the solvation effects


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were treated with the dielectric polarizable continuum model (DPCM), as implemented in Firefly.26 The optimized S0-min geometry of 9Me-6MeGua in water is nearly planar with a slight pyramidalization of amino group (Figure 1), and this is in accordance with previous OM2/MRCI studies on 9H-guanine.27 The S1 state mainly involve the orbital transition from HOMO to LUMO and the computed oscillator strength (in gas phase) is approximately 0.04. In the optimized S1-min geometry of 9Me-6MeGua, the amino group is not pyramidalized and stays mostly in the molecular plane, whereas the C6 atom is slightly puckered and the methoxy group goes out-of-plane. These results are in line with the TDDFT results of 6MeGuo by Ashwood and co-workers7 and indicated that the O6-methylation may play an important role in regulating the excited-state dynamics of Gua monomers. At the optimized S0-min and S1-min geometries, the vertical excitation and emission energies of 9Me-6MeGua in water were calculated with extended multiconfiguration quasidegenerate perturbation theory at second order of PT expansion (XMCQDPT2)28 method. The computed vertical excitation and emission energies of 9Me-6MeGua are 4.98 eV (249 nm) and 3.57 eV (347 nm), respectively. The deviations between these results and experimentally observed absorption (4.43 eV, 280 nm) and emission (3.26 eV, 380 nm) spectra of 6MeGuo in water are approximately 0.5 and 0.3 eV, respectively. Previous theoretical studies (see ref 29 and refs therein) have indicated that the computed vertical excitation energies of 9H-Gua by most of the theoretical methods, i.e. TDDFT with B3LYP and PBE0 functionals, CC2, CASPT2, and EOMEE-CCSD(T), range from 4.76 to 5.10 eV. Only when large active space (16e12o) and basis set (TZV+pol) are adopted, the obtained result (4.51 eV) is identical to the experimental value in water (4.51 eV).30 We then calculated vertical excitation and emission energies of 9Me-6MeGua by using XMCQDPT2 method with a large



basis set def2-TZVP, the obtained results are 4.79 and 3.39 eV, respectively. These results are in good agreement with the experimental results of 6MeGuo in water,7 and indicated that the selected model and the used methods in our calculations are reasonable. Figure 2A shows the located four MECIs between the S0 and S1 states of 9Me6MeGua in water at the SA2-CASSCF(10,9)/6-31G(d) level of theory, which can be divided into two types. The first (denoted as CI-C2-α) and the second (denoted as CIC2-β) MECIs are related to C2 reaction coordinate. CI-C2-α is characterized by a strong puckering of C2 atom and a slight distortion of the molecular plane. The strong puckering of the six-membered ring of CI-C2-β makes it exhibits a boat-like conformation and more pronounced ring distortion. The third (denoted as CI-C6-α) and the fourth (denoted as CI-C6-β) MECIs are associated with C6 reaction coordinate. Both CI-C6-α and CI-C6-β show a strong puckering of C6 atom and an out-of-plane motion of N1 atom. The six-membered ring distortion of CI-C6-α is more pronounced than that of CI-C6-β. The major difference between CI-C6-α and CI-C6-β is the direction of C6-O bond, which is parallel and perpendicular to the plane of fivemembered ring of CI-C6-α and CI-C6-β, respectively. Table 1 lists the CASSCF and XMCQDPT2 computed S0 and S1 energies of the four MECIs relative to the corresponding ground-state minimum energy. At the SA2CASSCF level, the CI-C2-α and CI-C6-α lie approximately 35.8 and 20.1 kcal/mol above the S1-min, respectively. The energy of CI-C2-β is essentially identical to the S1min, and the CI-C6-β lies approximately 5.1 kcal/mol below the S1-min. Therefore, the CI-C2-β and CI-C6-β are more energetically accessible than CI-C2-α and CI-C6-α. The energy order of the four MECIs does not change at the XMCQDPT2 level, however, the XMCQDPT2 computed energy differences between the S1-min and MECIs are


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larger approximately 7~14 kcal/mol than those of CASSCF. Moreover, for all the four MECIs, the XMCQDPT2 computed energy gaps between S0 and S1 states are slightly large. These may result from two reasons. First, the inclusion of dynamical correlation effects at the XMCQDPT2 level typically leads to an increasing of energy gap at the CASSCF optimized MECI points.6,31,32 Second, due to the limitation of the Firefly package26, the PCM model is only applied to CASSCF calculations. In this situation, although the modified one-electron Hamiltonian with PCM contributions from the CASSCF calculations is used in XMCQDPT2 calculations, the reaction filed will not be self-consistent at the XMCQDPT2 level. To assess which MECIs are energetically accessible and are responsible for excited-state decay of 9Me-6MeGua upon photoexcitation, we constructed the linearly interpolated internal coordinate (LIIC) pathways33,34 between the S1-min and four MECIs. The SA2-CASSCF(10,9)/6-31G(d) computed energy profiles along the constructed LIIC pathways are shown in Figure 2B. For both CI-C2-α and CI-C6-α, the energy is directly uphill from S1-min to MECI point. Moreover, the energies of CI-C2-α and CI-C6-α are larger than that of S1-min approximately 40 and 20 kcal/mol, respectively. Therefore, 9Me-6MeGua will not prefer to decay to the ground state through these two MECIs. The computed LIIC pathways for both CI-C2-β and CI-C6β (bottom of Figure 2B) show that the 9Me-6MeGua need to surmount an energy barrier to reach these two MECIs. Because the LIIC typically overestimate the energy barrier, we then optimized the transition states (TSs) between S1-min and these two MECIs with SA2-CASSCF(10,9)/6-31G(d). The frequency calculations were performed to confirm that each TS possesses only one imaginary frequency mode. Intrinsic reaction coordinate (IRC)35-37 calculation was then conducted to validate whether the corresponding reactant and product were S1-min and corresponding MECI, respectively.



The optimized geometries of the two TSs are shown in Figure 3A. The TSs between the S1-min and CI-C2-β and CI-C6-β are denoted as TS-C2-β and TS-C6-β, respectively. TS-C2-β is characterized by a distinct distortion of six-membered ring and a slight outof-plane motion of amino group. The puckering of the C2 atom and out-of-plane motion of amino group of TS-C2-β more closely resembles that of CI-C2-β. At the SA2CASSCF(10,9)/6-31G(d) level, TS-C2-β lies approximately 14.5 kcal/mol (Table 1) above the S1-min. This energy barrier is decreased to approximately 12.0 kcal/mol at the XMCQDPT2 level (Table 1). TS-C6-β has a strong out-of-motion of methoxy group that resembles that of CI-C6-β and a slight puckering of C6 atom. The computed energy barriers of TS-C6-β at the CASSCF and XMCQDPT2 levels are 6.7 and 7.8 kal/mol (Table 1), respectively. Based on our theoretical results, the excited-state relaxation decay mechanism of 9Me-6MeGua in aqueous solution was proposed as the following. Upon photoexcited to the S1 state, 9Me-6MeGua first relaxed to the S1-min (ππ*, La) accompanied by outof-plane motion of O6-methyl group. Because the experimentally measured fluorescence quantum yield of 6MeGuo in aqueous solution is only 0.4%,7 most of the populated excited state of 6MeGuo will return to its ground state through MECIs between the S0 and S1 states. Although there are four MECIs may be reached from S1min of 9Me-6MeGua, CI-C2-α and CI-C6-α should not be involved in the excited-state decay due to the high energy and uphill behavior from S1-min to MECI point (Figure 2B and 3B). Therefore, the populated S1-min of 9Me-6MeGua will relax to the ground state through two MECIs: CI-C2-β and CI-C6-β (Figures 3B and 4). To reach CI-C2-β and CI-C6-β, S1-min of 9Me-6MeGua need to overcome energy barriers approximately 14.51 and 6.85 kcal/mol (Figure 3B), respectively. This clearly indicated that the energy barrier of the C6 reaction coordinate of 6MeGuo is apparently low than that of the C2


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reaction coordinate. Therefore, the experimentally observed fast (~0.95 ps) and slow (~41 ps) decay of 6MeGuo should be assigned to the C6 and C2 reaction coordinate, respectively. This assignment is contrary to that of Ashwood and co-workers7 and indicated that their proposed mechanism need to be revised. Although most of the previous experimental and theoretical studies proposed that the C2 reaction coordinate is the primary decay pathways of guanosine monophosphate (GMP),23,38 2′deoxyguanosine 5′-monophosphate (dGMP),22,25 and Gua.39-43 Recent theoretical study on 9H-Gua has revealed that both the C2 and C6 reaction coordinates are involved and the latter plays a major role in solution.27 Moreover, the optimized MECI between S0 and S1 states of 6-enolguanine (6-EnolGua) by earlier theoretical studies39,40 is characterized by out-of-motion of hydroxy at the C6 position. Our theoretical results further demonstrated that the C6 reaction coordinate is the dominant relaxation pathway of 6MeGuo and this relaxation process occurs on a fast timescale (~0.95 ps).7 Comparing with the GMP23,38 and dGMP, 22,25 where only fast internal conversion (IC, ~1 ps) process through C2 reaction coordinate was observed, the rate of the IC process of 6MeGuo was decreased by ~40 fold.7 According to our calculation results, this is because that the energy barrier of C2 reaction coordinate of 6MeGuo is increased by O6-methylation. It should be noted that the ultrafast decay of 9Me-6MeGua may happen before the intramolecular vibrational relaxation (IVR). In this situation, it goes over the barrier directly and does not involve the S1 minimum. Therefore, it is necessary to compare the energies of TSs and MECIs with respect to the Franck-Condon (FC) point on the S1 state. The results are shown in Figure S2. Figure S2 reveals that the relaxation from FC to CI-C6-β can be regarded as barrierless and from FC to CI-C2-β, 9Me-6MeGua need to overcome a barrier approximately 6.9 kcal/mol. The energies of CI-C2-α and CI-C6-



α are still larger than that of FC point approximately 28.2 and 12.5 kcal/mol, respectively. At the XMCQDPT2 level (see Table 1 and Figure S3), it seems that both the ultrafast decays from FC to CI-C6-β and CI-C2-β can be regarded as barrierless. Moreover, CI-C6-α may also be involved in the ultrafast decay because it only larger than that of FC point approximately 3.9 kcal/mol. However, in any case, the C6 reaction way is faster than the C2 reaction way and plays a more important role in the ultrafast decay of 9Me-6MeGua. Finally, to assess the solvation effects on the PES of 9Me-6MeGua, we also optimized the geometries of the ground and first excited states, MECIs, and TSs of 6MeGua in gas phase. In Table S1 we list the calculated energies of each configuration in gas phase. Comparing the results in Table S1 with those of in Table 1, one can see that the solvation has obvious effect on the emission energy, which is red-shifted approximately 0.26 eV from gas phase to aqueous solution. In addition, in gas phase, the XMCQDPT2 computed energy difference between TS-C2-β and TS-C6-β is only 1.6 kcal/mol, and this value increases to 4.3 kcal/mol in water. These results indicated that the solution will further slowdown the C2 reaction pathway. Moreover, the intermolecular hydrogen bonding44 may affect the PES and this need further studies. Conclusions In summary, by employing the CASSCF and XMCQDPT2 methods with implicit solvation model, we provide a complete and detailed mechanism for the excited-state relaxation of 6MeGuo in aqueous solution, as is shown in Figure 4. The experimentally observed fast and slow decay processes of 6MeGuo7 are reassigned to C6 and C2 reaction coordinates, respectively. For the first time, we demonstrated that O6methylation not only makes the C6 reaction coordinate become the primary decay pathway, but also increases the energy barrier of the C2 reaction coordinate, thereby


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slows down the IC process. Therefore, this study provides a fundamental insight into the excited-state decay mechanism of 6MeGuo and illustrates the effects of O6methylation on regulating the photochemistry of guanine monomers.

Supporting Information. The following materials are provided: computational details, orbitals involved in the (10,9) active space, and all the optimized geometries. Acknowledgements We are grateful to the National Natural Science Foundation of China (Grant No: 21773238 and 21503224).

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Table 1. SA2-CASSCF and XMCQDPT2 computed the ground and first excited-state energies of the S0-min, S1-min, MECIs and TS (in kcal/mol) in water, where the ground state energy of the S0-min was set to zero.

S0-min S1-min CI-C2-α CI-C2-β CI-C6-α CI-C6-β TS-C2-β TS-C6-β

CASSCF XMCQDPT2 S0 S1 S0 S1 0.00 126.7 0.00 115.0 25.9 119.1 17.6 100.1 154.3 154.9 132.0 145.0 119.3 119.9 94.3 114.1 139.1 139.2 113.5 118.9 113.5 114.1 81.7 103.0 42.1 133.7 28.0 112.2 80.9 126.0 65.0 107.9



Figure 1. Schematic picture of 9Me-6MeGua (top) and the SA2-CASSCF(10,9)/631G(d) optimized geometries of the ground and first excited states of 9Me-6MeGua (bottom).

Figure 2. (A). Geometries of the four MECIs optimized at the SA2-CASSCF(10,9)/631G(d) level. (B). Computed energy profiles along the constructed LIIC pathways between the S1-min and four MECIs with SA2-CASSCF(10,9)/6-31G(d).


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Figure 3. (A). Geometries of the two TSs optimized at the SA2-CASSCF(10,9)/631G(d) level. (B). SA2-CASSCF(10,9)/6-31G(d) computed energy diagram for 9Me6MeGua in water at the first excited-state.

Figure 4. Proposed mechanism of the excited-state relaxation of 9Me-6MeGuo in water.



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How Does the O6-Methylation Regulate the Excited-State Decay of

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