DNA (6−4) Photolesion Repair Occurs in the Electronic Ground State

Aug 12, 2010 - DNA (6−4) Photolesion Repair Occurs in the Electronic Ground State of the TT Dinucleotide Dimer Radical Anion. Citing Articles; Relat...
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DNA (6-4) Photolesion Repair Occurs in the Electronic Ground State of the TT Dinucleotide Dimer Radical Anion Philipp H. P. Harbach, Julia Borowka, Mercedes-Vanessa Bohnwagner, and Andreas Dreuw* Institut f€ ur Physikalische und Theoretische Chemie, Goethe-Universit€ at Frankfurt, Max-von-Laue-Str. 7, D -60438 Frankfurt (Main), Germany

ABSTRACT (6-4) Photolyases are enzymes utilizing light to repair DNA pyrimidine-pyrimidone photolesions. The first step of enzyme function involves absorption of a photon and electron transfer from a flavin adenine dinucleotide anion (FADH-) to the (6-4) lesion-inducing repair, that is, splitting of the covalently bound nucleobase dimer. Here we demonstrate that the repair mechanism occurs in the electronic ground state of the lesion radical anion because the initially absorbed photon energy is not sufficient to initiate electron transfer and to excite electronically the radical anion of the (6-4) lesion simultaneously. SECTION Dynamics, Clusters, Excited States

D

NA is well known to be damaged by solar UV radiation.1 The pyrimidine bases thymine and cytosine can undergo dimerization upon photoexcitation into electronically excited states. The most relevant DNA damages are the cyclobutane pyrimidine dimer (CPD) and the pyrimidine-pyrimidone (6-4) lesions both being mutagenic and carcinogenic.2-5 Therefore, efficient repair of these photodamages of DNA is inevitable and is accomplished in many organisms by repair enzymes, including the so-called photolyases.6,7 Astonishingly, these enzymes also utilize light for the repair of DNA photo damages.8 The underlying mechanism is assumed to proceed in two successive steps: (1) photoinduced electron transfer and (2) electron-induced repair of the lesion.9-12 Photolyases contain the deprotonated form of 1,5-dihydroflavin adenine dinucleotide (FADH-) as a catalytic cofactor and a light-harvesting photoantenna that may be either 8-hydroxy-5-deazaflavin (8-HDF) or 5,10methenyltetrahydrofolate (MTHF) depending on the type of photolyase.13,14 Whereas the latter act as antennas absorbing the photon, FADH- is usually the electron donor and transfers the electron to the photolesion triggering damage repair, that is, lesion splitting. The initial photoinduced electron transfer step is very efficient with a quantum yield near unity.15 Recently, the structure of (6-4) photolyase from Drosophila melanogaster has been resolved (Figure 1), and only one FADH- chromophore and no light-harvesting photoantenna is present.13 However, recently, it has been shown that this photolyase uses 8-hydroxy-5-deazaflavin as a photoantenna.16 Thus, FADH- is excited by energy transfer from the antenna pigment, and photoinitiated electron transfer to the nearby T(6-4)T-lesion generates an FADH radical and a lesion radical anion in their respective electronic ground states according to Scheme 1. Currently, theoretical and experimental effort is undertaken to unravel the details of the repair mechanism following the electron transfer.9,17-22 It has been suggested that repair

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may proceed via thermal formation of an oxetane intermediate and subsequent electron transfer,23,18,25 but recent experimental and theoretical evidence point toward a mechanism avoiding the formation of an oxetane ring.13,24 Computed energy barriers for the latter mechanism are still too high to explain DNA repair; however, calculations have shown that the nonoxetane mechanism can proceed barrierless via a conical intersection, when the generated lesion radical anion is promoted into its first excited electronic state.19 This, however, is energetically only feasible if the initially absorbed photon energy is high enough not only to initiate the electron transfer but also to excite the formed lesion radical anion electronically (Scheme 2). An alternative to excite the T(6-4)T photolesion radical anion is in principle by absorption of a second photon. In this contribution, we demonstrate that the first scenario (Scheme 2) is energetically impossible; that is, the energy of one absorbed photon by FADH- is not sufficient to transfer an electron and to excite the lesion simultaneously. A two-photon process is not relevant because of the low photon flux density of solar radiation under natural conditions. In the described two-photon process, a first photon is absorbed by FADH- to generate the lesion radical anion, and shortly afterward, a second one electronically excites the lesion radical anion. The photon flux density of solar radiation at the Earth's surface is ∼2  1021 m-2 s-1,25,26 in the range where FADH- and the lesion absorb. To estimate an upper bound safely for the necessary lifetime of the lesion radical anion to absorb a second photon, a photon flux density of 1022 m-2 s-1 and an effective absorbing surface of 1 nm2 of the lesion are assumed, which are significantly larger than the real

Received Date: July 1, 2010 Accepted Date: August 5, 2010 Published on Web Date: August 12, 2010

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Figure 1. Structure of photodamaged DNA (right, wires) bound to (6-4) photolyase (left, ribbons). The FADH- photoreceptor (blue) and the (6-4) DNA photolesion (red) are visible in the center.

Figure 2. Molecular structure of the reduced form of the flavin adenine dinucleotide (FADH-).

Scheme 1

Scheme 2

values. Thereby one arrives at an upper bound for the flux density of at most one UV photon per millisecond at the lesion under natural conditions. In other words, the radical anion of the lesion must live significantly longer than 1 ms to be excited into the S1 state via absorption of a second photon. However, 1 ms is a very long lifetime for a reactive species like a radical anion representing an electronic excited state. Therefore, two-photon processes can be safely excluded from being of any relevance for the repair of DNA lesions. After having excluded two-photon processes as an efficient source of electronically excited lesion radical anions, let us now investigate the possibility of an excited FADH- to transfer an electron to the lesion and to excite it simultaneously (Scheme 2). The obvious question to answer is whether the energy deposited by the photon exciting FADH- is enough to accomplish both. Therefore, one needs to know the excitation energies ωex of FADH- and the (6-4) lesion radical anion in their corresponding protein environments as well as the ionization potential (IP) of FADH- and the electron affinity (EA) of the lesion. Then, the reaction energy is given by

Figure 3. (a) Structure of the DNA (6-4) photolesion model of a thymine-thymine base pair exhibiting two deoxyriboses and the phosphate backbone and (b) reduced molecular model with the backbone omitted and replaced by methyl groups. Table 1. Ionization Potential (IP) of FADH- and the Electron Affinity (EA) of the (6-4) Photolesion Calculated at the DFT/ B3LYP Level of Theory in the Gas Phase and in a Dielectric Continuum with Increasing Dielectric Constant ε from 0 (Gas Phase) up to 80 (Water)a ε=5

ε = 10

ε = 20

ε = 80

IP (FADH )

1.95 2.37b

2.20

2.35

2.40

2.43

2.45

EA (lesion)

0.21 0.01b

0.45

0.60

0.65

0.67

0.69

All energies are given in electronvolts. b SOS-MP2/6-31G*.

respectively (Table 1). Inclusion of the protein environment as a dielectric continuum in our computations demonstrates that its influence on the IP and EA is not very large. With increasing dielectric constant from ε = 2 to 80, the IP of FADH- and the EAof the lesion gradually increase up to values of 2.45 and 0.69 eV; that is, both increase by ∼0.5 eV (Table 1). This is not surprising because one can expect a polar environment to stabilize charged species. To confirm the reliability of the computed values at DFT level, we have employed SOS-MP2 to recompute the gas-phase values. At SOS-MP2 level, they are 2.37 and 0.01 eV for the IP of FADHand the EA of the lesion, respectively. On the basis of the

ð1Þ

If ΔEETX is positive, then the energy is sufficient to transfer the electron and to excite the lesion radical anion electronically. The energy ΔEET to only transfer an electron but not to excite the radical lesion is also given by eq 1, but ωex(lesion-) is set to zero. The IP of FADH- and the EA of the lesion have been calculated at their equilibrium geometries (Figures 2 and 3) and have values of 1.95 and 0.21 eV in the gas phase,

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ε=2

a

ΔE ETX ¼ ωex ðFADH - Þ - ωex ðlesion - Þ - IPðFADH - Þ þ EAðlesionÞ

gas phase -

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Table 2. Ten Lowest Excited Singlet States of FADH- Calculated at the Theoretical Level of TDDFT/B3LYP Using the Standard 6-31G* Basis Seta state

gas phase

ε=2

ε=5

ε = 10

ε = 20

ε = 80

S1

1.27 (0.00)

1.33 (0.00)

1.38 (0.00)

1.40 (0.00)

1.41 (0.00)

1.42 (0.00)

S2

1.52 (0.00)

1.55 (0.00)

1.57 (0.00)

1.58 (0.00)

1.59 (0.00)

1.59 (0.00) 2.24 (0.00)

S3

2.10 (0.00)

2.16 (0.00)

2.21 (0.00)

2.22 (0.00)

2.24 (0.00)

S4

2.24 (0.00)

2.27 (0.00)

2.29 (0.00)

2.30 (0.00)

2.31 (0.00)

2.31 (0.00)

S5

2.63 (0.00)

2.63 (0.00)

2.63 (0.00)

2.63 (0.00)

2.63 (0.00)

2.63 (0.00)

S6

3.02 (0.00)

3.07 (0.00)

3.11 (0.00)

3.13 (0.00)

3.14 (0.00)

3.14 (0.00)

S7 S8

3.12 (0.00) 3.21 (0.09)

3.18 (0.00) 3.22 (0.11)

3.22 (0.11) 3.23 (0.00)

3.22 (0.11) 3.25 (0.00)

3.22 (0.11) 3.26 (0.00)

3.22 (0.11) 3.26 (0.00)

S9

3.22 (0.03)

3.27 (0.00)

3.31 (0.00)

3.32 (0.00)

3.33 (0.00)

3.34 (0.00)

S10

3.34 (0.00)

3.37 (0.00)

3.40 (0.00)

3.41 (0.00)

3.41 (0.00)

3.42 (0.00)

a

To estimate the influence of a polar environment, a dielectric continuum model has been included into the calculations with increasing dielectric constant from ε = 2 to 80. All excitation energies are given in electronvolts; oscillator strength is given in parentheses.

Table 3. Vertical Excitation Energies of the Five Energetically Lowest Singlet States of the Radical Anion of the T(6-4)T Photolesiona

results of our computations so far, one can safely assume that it will cost ∼2.3 eV to remove the electron from FADH- and that one will gain at most 0.5 eV from attaching it to the lesion. Therefore, altogether the electron transfer from FADH- to the lesion requires at least ∼1.8 eV. To conclude finally whether the repair of the DNAT(6-4)T lesion can occur in the first excited state of the lesion radical anion, we have calculated the vertical excited states of FADHand the lesion radical anion at the level of time-dependent density functional theory (TDDFT) using the molecular models depicted in Figures 2 and 3. For computationally less demanding TDDFT, a larger molecular model can be applied, which also contains parts of the DNA backbone. Going to more demanding and more accurate wave-function-based methods, a smaller model neglecting the DNA backbone must be used. Whereas FADH- can be expected to be described very well by TDDFT because it is closed-shell and a planar pigment not prone to intramolecular charge transfer, the open-shell lesion radical anion will pose a challenge to TDDFT because of its dimeric nature and the concomitant tendency to yield spurious charge-transfer states in TDDFT.26 The excitation energies of the 10 energetically lowest states of FADH- do not largely change at the theoretical level of TDDFT when xc functionals with increasing amount of Hartree-Fock exchange are employed. One does observe the typical blue shift of all states to higher excitation energies when the fraction of HF exchange is increased from 0 (BLYP) to 20% (B3LYP) and finally 50% (BHLYP), but the order of states remains essentially the same. Most importantly, the lowest bright state of FADH- exhibiting noticeable oscillator strength is found as the S8 state in the gas phase at an energy of 3.21 eV at the ground-state equilibrium geometry of the FADH- corresponding to an excitation wavelength of ∼390 nm (Table 2). This state absorbs in the UV region and thus corresponds most likely to the one responsible for the initial excitation of FADH- in the photolyase. Experimentally, the absorption spectrum of the (6-4) photolyase exhibits an absorption maximum at 400 nm,27 which is in good agreement with our computed TDDFT/B3LYP value. To illuminate the influence of a polar environment onto this excited state, we have also performed the excited-state calculations in a

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state

BLYPb

B3LYPb

BHLYPb

BHLYPc

CIS(D)c

ADC2c

CC2c

D1

0.38

0.53

2.38

1.95

1.55

1.63

1.61

D2

0.72

0.88

3.22

2.97

2.15

2.07

2.01

D3 D4

1.83 1.98

2.14 2.40

3.84 4.31

4.16 4.48

2.81 2.96

2.77 3.10

2.66 2.96

D5

2.19

2.69

4.39

4.80

3.81

3.75

3.62

a

All energies are given in electronvolts. The four lowest excited states of the lesion radical anion exhibit oscillator strength of ∼0.015 consistently at all employed levels of theory. Note that only the D1 and D2 states of the lesion model and the reduced model are directly related. b Calculated for lesion model of the T(6-4)T photolesion depicted in Figure 3a. c Calculated for a reduced molecular model of the T(6-4)T photolesion (Figure 3b).

dielectric continuum by analogy to the calculations of the IP and EA described above. In Table 2, one can easily see that the influence of the dielectric continuum onto the excited states is negligible. On the basis of our calculations and the experimental value, it is safe to assume that photochemical energy of ∼3.2 eV is available through the initial excitation of FADH-. The computation of the vertical excited states of the radical anion of the T(6-4)T-photolesion is problematic with TDDFT because of its dimeric structure. It is well known and well documented that TDDFT underestimates the energies of charge-transfer excited states drastically by several electronvolts in weakly bound complexes.26 Therefore, one can expect these states to occur in the low-energy region of the spectrum of the radical anion. However, because of the size of the chosen model including parts of the DNA backbone, TDDFT is the only computationally feasible approach. A clear indication that the lowest excited states are indeed affected by the charge transfer problem is the fact that the states are drastically shifted to higher excitation energies from 0.38 to 0.53 and 2.38 eV with increasing amount of nonlocal Hartree-Fock exchange in the employed xc functional when going from BLYP to B3LYP and BHLYP, respectively (Table 3). At the level of SOS-CIS(D), the excitation energy of the lowest excited state of the lesion radical anion is found to be even

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higher with 2.68 eV. For further corroboration, the vertical excited states of the radical anion of a smaller molecular model of the lesion (Figure 2b) have been computed using unrestricted wave-function-based CIS(D), ADC(2), and CC2 methods (Table 2). At these levels of theory, the lowest excited state possesses excitation energies of ∼1.6 eV, whereas SOS-CIS(D) gives a value of 2.34 eV. Comparison of the excitation energies of the radical anions of the larger and smaller lesion models at the BHLYP and SOS-CIS(D) levels reveals the D1 excitation energy to be reduced by roughly 0.4 eV in the smaller model. In addition, a polar environment has been simulated by the inclusion of a dielectric continuum with increasing dielectric constant from ε = 2 to 80, and by analogy to the previous results for FADH-, the influence is essentially negligible. From these calculations, one can safely conclude that the vertical excitation energy of the lowest excited state of the lesion radical anion exhibits a value of ∼2 eV, which is also in agreement with values previously reported at the CISD level of theory.19 Finally, ΔEETX and ΔEET can be calculated with eq 1 inserting the computed values of the individual quantities. The computed IP of FADH- is 2.3 eV, the EA of the lesion 0.5 eV, and the vertical excitation energies of FADH- and the lesion radical anion have been calculated to be 3.2 and 2 eV, respectively. Altogether, this yields upper bounds for the values of -0.6 eV for ΔEETX and 1.4 eV for ΔEET, keeping in mind that we have estimated all values in favor of large values of ΔEETX and ΔEET. Furthermore, energy loss due to dissipation is not considered at all within eq 1, which can be expected to be significant, making the electronic excitation of the lesion radical anion even more unlikely. Although our analysis relies on electronic energies only and free energies should be compared, one can expect the main conclusion to be valid because the changes in geometry are only very small for the neutral and anionic species. In summary, one can definitely conclude that the initial excitation energy of FADH- suffices to initiate the electron transfer to the lesion (ΔEET > 0) but not to simultaneously excite the generated radical anion of the lesion (ΔEETX < 0). Therefore, the repair mechanism of DNA (6-4) photolesions by photolyases must proceed in the electronic ground state of the latter. Our findings and the fact that the reported thermal activation energies for photolesion repair via nonoxetane pathways are high19 seem to be in line with repair mechanisms via thermal oxetane intermediate formation.

been modeled by inclusion of a dielectric continuum into our calculations, utilizing a self-consistent reaction field approach. The dielectric constant was chosen to be ε = 2, 5, 10, 20, and 80 ranging from weakly polar to extremely polar media. The vertical excited states of FADH- and the lesion radical anion have been computed with TDDFT30,31 in combination with the BLYP, B3LYP, and BHLYP xc functionals and the 6-31G* basis set to identify possible problems with chargetransfer excited states.26 For a reduced molecular model of the lesion radical anion, the excited states have also been calculated with the configuration interaction singles plus perturbative doubles (CIS(D)) as well as its scaled oppositespin variant SOS-CIS(D), the algebraic diagrammatic construction approach of second order (ADC(2)), and the approximate coupled cluster approach of second order (CC2), as implemented in the Q-Chem 3.2 suite of quantum chemical programs.32 Whereas for the calculations of FADH- restricted versions of the above-mentioned methods have been employed, the calculations on the radical anion of the lesion dimer have been performed with the corresponding unrestricted implementations.

AUTHOR INFORMATION Corresponding Author: *To whom correspondence should be addressed. E-mail: andreas. [email protected].

ACKNOWLEDGMENT A.D.

acknowledges funding by the Deutsche Forschungsgemeinschaft as a Heisenberg-Professor. Computation time has been generously provided by the Center of Scientific Computing of the University of Frankfurt.

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COMPUTATIONAL DETAILS The crystal structure of (6-4) DNA-photolyase of Drosophila melanogaster served as input for our theoretical investigation.13 Nonresolved hydrogen atoms were added to the experimental structures of FADH- and the (6-4) photolesion and optimized using standard Kohn-Sham density functional theory (DFT) with the Becke three-parameter Lee-Yang-Parr (B3LYP) xc functional and the 6-31G* basis set. For these structures, the IP of FADH- as well as the EA of the (6-4) lesion have been calculated with standard DFT/B3LYP and scaled opposite-spin Møller-Plesset perturbation theory of second order (SOS-MP2).28,29 The influence of a polar environment, that is, the protein, onto the IP and EA values has

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