Benzophenone and DNA: Evidence for a Double Insertion Mode and

Letter pubs.acs.org/JPCL

Benzophenone and DNA: Evidence for a Double Insertion Mode and Its Spectral Signature Elise Dumont*,† and Antonio Monari*,‡,§ †

Laboratoire de Chimie, UMR 5182 CNRS, Ecole Normale Supérieure de Lyon, 46 allée d’Italie, 69364 Lyon, Cedex 07, France Théorie-Modélisation-Simulation, Université de Lorraine − Nancy, SRSMC Boulevard des Aiguillettes, Vandoeuvre-lès-Nancy, Nancy, France § Théorie-Modélisation-Simulation, CNRS, SRSMC Boulevard des Aiguillettes, Vandoeuvre-lès-Nancy, Nancy, France ‡

S Supporting Information *

ABSTRACT: From explicit solvent molecular dynamics simulations, we probe the existence of two stable and competitive interaction modes between an alternating poly(dA-dT) decamer and benzophenone, a minor groove adduct and a double insertion structure in which the central base pair is ejected, with hydrogen bonding with proximal groups, locking the DNA−drug complex. The extensive analysis of noncovalent interactions provides a rationale for the existence of this mode, never reported yet between DNA and any organic photosensitizer. We evidence a highly characteristic signature in our simulated circular dichroism spectra that may provide useful guidance for the future experimental efforts, as well as for theoretical investigations aiming at elucidating the energy-transfer mechanism between benzophenone and thymines. SECTION: Biophysical Chemistry and Biomolecules

D

resolution structures lacking,9 but also more indirect proof based, for instance, on fluorescence-based assays and circular dichroism (CD)10,11 are still absent. A complete characterization of DNA binding agents and of photosensitization begins with a clear structural picture, at the atomic scale, of their interaction mode(s) to DNA. Classical or quantum mechanical12 modeling has proven its efficiency as a “computational microscope” 13 to unravel key features of DNA−drug interactions and can be regarded as complementary to experimental structure characterization. To the best of our knowledge, even clear structural pictures of possible DNA−BP adducts based on molecular dynamics (MD) simulations are currently missing. In this Letter, we identify and characterize two stable interaction modes of BP with DNA. Our study relies on explicit solvent MD simulations combined with a density functional theory (DFT) analysis of the noncovalent interactions (NCIs) that stabilize or do not stabilize the complex (see the Computational Section). In addition to minor groove binding, we evidence and we report here for the first time a novel interaction mode that we refer to as “double insertion”, in which BP ejects two paired nucleobases to substitute both of them in the B-DNA stacked structure. Additionally, we also determine the UV/vis- and CD-specific spectroscopic signatures by using a hybrid quantum mechanics/molecular mechanics (QM/MM) scheme that takes into account the

NA is optimized to maintain genome integrity, yet its intrinsic photostability1 is threatened upon constant exposure to electromagnetic radiation, which inevitably generates deleterious photoinduced lesions.2 UVB radiation (280−320 nm, 0.3% of the sunlight) is well-known to generate photodefects, notably pyrimidine dimers. Less energetic UVA radiation (320−400 nm, 5.1% of the sunlight) also produces various DNA lesions, either directly3 or indirectly via photosensitization.4 Photosensitizers are relatively small molecules interacting with DNA and behaving as intermediates; they absorb UV light, and then induce energy transfer through an antenna effect. Most often, excited triplet states play a key role in this process.5,6 Photosensitization not only expands the number of UVA-produced defects but also strongly enlarges the spectral width generating harmful effects to DNA, that can thus reach visible wavelengths. An in-depth understanding of the mechanism of the DNA− drug interaction is of fundamental importance and opens the door for designing more effective and less toxic photosensitizers. Real-time monitoring of photoinduced energyand electron-transfer processes has been recently accomplished for some DNA−drug complexes by combining high-level timeresolved spectroscopies7 but remains a real scientific challenge. Indeed, even an experimental 3D structure of the DNA−drug adduct is still lacking for common toxic photosensitizers such as benzophenone (BP, Figure 1). This prototypical small organic molecule has a high affinity to DNA and triggers lesions upon exposure to light,8 principally on thymine bases. In particular, for DNA−BP interaction, not only are nuclear magnetic resonance (NMR) or X-ray high© 2013 American Chemical Society

Received: October 4, 2013 Accepted: November 20, 2013 Published: November 20, 2013 4119

dx.doi.org/10.1021/jz4021475 | J. Phys. Chem. Lett. 2013, 4, 4119−4124

The Journal of Physical Chemistry Letters

Letter

Figure 1. (a) BP structure: BP is a nonplanar aromatic drug showing a high affinity for DNA, with a triplet-state energy transfer to thymines. (b) The proximity of H2 and H2′ triggers BP nonplanarity. (c) This deviation is measured by the dihedral τ defined between C2, C1, C1′, and C2′.

Table 1. Structural and Energetic Characterization of Representative Snapshots for DNA−BP Complexesa decomposition of the NCIs ΔE (kcal/mol)

ΔE (kcal/mol)

−11.0 (−16.0)

−10.7 (−20.0)

vertical

DNA−BP mode major (t = 0 ns)

snapshot number 0

relaxed

(Figure S1Supporting Information) minor (t = 20 ns)

4999

−16.5 (−20.5)

−18.8 (−39.6)

(Figure 2)

classic insertion (t = 8.4 ns)

2091

−22.2b (−29.0)

−3.4c (−42.1)

(Figure S4Supporting Information)

double insertion (t = 20 ns)

4999

−26.2 (−39.6) b

−15.4 (−52.2) c

(Figure 3)

atoms

distance

energy

nature

H4(BP)···Hm(T4)

2.26

−1.1

Disp.

H2(BP)···Hm(T6); H3(BP)···Hm(T6)

−1.7

Disp.

H5′(BP)···Hm(T14) H3(BP)···O2(T16)

2.45, 2.93 2.42 2.87

−1.9 −1.7

Disp. weak HB

H3′(BP)···O2(T4) H2′(BP)···N3(A5) H2(BP)···N3(A17) H3′(BP)···O4(T16)

3.45 2.72 3.03 2.70

−0.7 −1.8 −1.9 −0.4

weak weak weak weak

H6(A5)···OP(A3-T4)

2.49

−1.7

weak HB

H5(BP)···N3(A5); H5(BP)···C4(A5)

−1.5

H4(BP)···C4(A5)

2.43, 3.06 3.31

−1.1

HB and CH π-ar. CH π-ar.

X′(BP)···X(T16)d O2(T16)···H6(A17) H6(A5)···OP(A3-T4)

3.42 2.29 1.76

−1.2e −4.6 −7.4

Disp. HB HB

HB HB HB HB

a

Energies in kcal/mol are evaluated on subfragments (see the Supporting Information); the dispersion component is indicated in parentheses. The individual contributions are qualified as dispersive (Disp.), the CH···π-aromatic ring, (weak), and HB for hydrogen bonds. The numbering of the atoms is specified in the corresponding figures. bComputed with respect to the decamer with one or two nucleobases flipped (respectively for the classic and double insertion). cComputed with respect to the decamer with A-T not flipped (same optimized structure as those for the groove binding). For the sake of comparison, the Watson−Crick association between thymine and adenine accounts for 12 kcal/mol at the same level of theory. dX and X′, respectively, denote the barycenter of T16 and of the BP ring close facing T16. eThe angle between the two normal vectors of the BP′ cycle and T16 is stable at around 30°.

environmental effects in tuning spectroscopic response.14−16 Thanks to our predictions, these specific binding modes could be easily detected and their role in the generation of photodefects elucidated. Thus, our results provide a guideline for future experiments on the DNA−BP interaction, as well as starting structures for further modeling studies of the photoinduced energy- and electron-transfer processes. Initial structures were generated for a BP moiety interacting with an explicitly solvated alternating poly(dA-dT) decamer for the four conventional interaction modes, intercalation, insertion, minor, and major groove binding (see the Supporting Information). Along the 20 ns MD trajectories, only two out of four adducts are predicted to be stable complexes; the minor groove binding kept a conformation close to the starting one, while the insertion mode evolved toward the double-inserted structure. On the other hand, major groove binding and intercalation conformations were unstable and led to the DNA−BP aggregate disruption.

It is insightful to start by analyzing the lack of affinity between BP and the major groove. The initial structure represented in Figure S1 (Supporting Information) presents attractive dispersive interactions (green isodensities in the NCI analysis plot), amounting to −16 kcal/mol (see Table 1), but a stronger attraction pattern, such as hydrogen bonds (HBs), cannot take place between BP and electron-withdrawing groups of the nucleobases. Their formation is prevented by the proximity of the methyl groups of three thymines T4, T6, and T14, which are slightly attractive but would become repulsive at shorter range. The absence of a HB induces an inherent instability, resulting in adduct dissociation after ∼9 ns. In contrast, BP is found to stably interact with the B-DNA minor groove (Figure 2). The stabilization arising from London forces is comparable to the major groove situation (−20.5 kcal/ mol for the unrelaxed geometry at the end of the MD trajectory). However, it becomes twice that after full geometry relaxation, thus indicating an intrinsically greater stability when lying in the minor groove. Most importantly, cooperative 4120



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Figure 2. (a) Cartoon representation of the final conformation of BP lying in the minor groove of the poly(dA-dT) decamer. (b) Side view of the dispersive interactions maintained between the two base pairs. (c) Top view showing the four weak NCIs with BP; time evolutions are given in Figure S2 (Supporting Information). The s = 0.5 au isosurface is colored according to a BGR scheme over the range −0.05 < sin(λ2)ρ < 0.05.

Figure 3. (a) Cartoon representations of the final conformation of BP inserted. (b) Side view: a global NCI view showing the dispersive interactions between BP and the surrounding base pairs is given in Figure S5 (Supporting Information). (c) The stabilization of the double insertion mode also relies on two HBs locking the ejected A5 and T16. The s = 0.5 au isosurface is colored according to a BGR scheme over the range −0.05 < sin(λ2)ρ < 0.05.

interactions progressively take place along the trajectory; after ∼9 ns, the DNA−drug complex forms two asymmetric weak HBs between the hydrogens H3 and H3′ of BP and the oxygens O2 of thymines T4 and T16. In this conformation, BP also develops a weak HB with the spatially close adenines A5 and A17, and it shows no concomitant dihedral compression (τ ≈ −35°, i.e., close to the reference value, see Figures S2 and S6 (Supporting Information)). BP−adenine HBs imply hydrogens H2 and H2′ and nitrogens N3 of the two central adenines, which are slightly stronger than BP−thymine ones (−2 kcal/mol; see Table 1). Interestingly this stabilization mechanism based on the HB network clearly favors the sliding of the drug through the minor groove. This sliding motion is particularly important

because it leads to the possibility for BP to access different DNA bases that could be photosensitized.17 The insertion starting conformation evolves toward a double insertion mode, with either A5 or T16 initially ejected and the complementary base being also flipped out of the helix during the 20 ns trajectories (Figures S3 and S4, Supporting Information). The metastable nature of the insertion is manifest because the adiabatic stabilization energy only accounts for −3.4 kcal.mol−1. However, fully inserting the bicyclic drug in between {T4-A17} and {T6-A15} base pairs (double insertion) is associated to a gain of ∼−12 kcal.mol−1 (Table 1). This additional increment is indeed sufficient to lead to a stable adduct. Stabilization is due to a reinforced dispersion, which can be visualized from the NCI analysis in Figure 3, but also on 4121



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Figure 4. Simulated CD spectra for BP in minor-groove-bound (left) or double-inserted (right) with the alternating poly(dA-dT) decamer. One distinguishes the signals of the Λ and Δ entities.

structural differences between the two interaction modes and to reveal any BP−DNA interaction. This also holds for the absorption spectra of the ejected nucleobases A5 and T16 in the double-inserted mode that are still similar to the one of adenine and thymine in solution, Figure S10 (Supporting Information), and in regular B-DNA, Figure S11 (Supporting Information). However, the interaction of a given drug with a chiral macromolecular environment can result in induced CD, a property largely exploited to monitor interaction with biological macromolecules.22−26 BP presents an inherent axial chirality, resulting in two different enantiomers Λ or Δ. Upon minor groove binding (Figure 4 left), we found that the overall CD spectrum is dark due to reciprocal signal cancellation of the positive and negative rotational strengths of the Δ and Λ enantiomers, such as in water solution (Figure S8, Supporting Information). However, in the double-inserted interaction mode, DNA exerts a stronger influence on BP, as clearly shown on the computed27 CD spectra reported in Figure 4 right. Both enantiomers give rise to negative rotational strength at ∼350 nm. Also, the near-UV region has weaker but positive rotatory strengths for both Δ and Λ trajectories. Hence, a striking difference is revealed between the two interaction modes as only the double-inserted adduct shows a very intense and characteristic induced CD signature, appearing far from the DNA absorption region. We show that the strong DNA−BP interplay in the double insertion mode also has an implication on the DNA CD spectra (Figures S10 and S11, Supporting Information), which does not show the typical largely positive band of the A-T double strand but a rather complex structure ranging from 200 to 270 nm. This provides an interesting footprint of its interaction with BP for the double insertion mode. Additionally, we performed a natural orbital analysis (NTO)28,29 of the triplet excited states that evidences electronic density delocalization and surmises ET feasibility (see Figure S12, Supporting Information) between BP and a vicinal thymine base. It is noteworthy that the triplet delocalization appears to be equivalent for the geometries representative of the final structures of the minor-groove-bound and double-inserted modes. In conclusion, we have probed the existence of two stable interaction modes between BP and an alternating poly(dA-dT) sequence based on explicit solvent MD simulations. NCIs govern the stability of the DNA−BP adduct, with dispersion

hydrogen bonding between the ejected bases and proximal DNA groups. These HBs take place between O2(T16) and H6(A17) (amino group) and H6(A5) and O(P), one available oxygen atom of the phosphate group linking T3 and A4 (Figure 3c). They form a stronger stabilization pattern than the four interactions listed for the minor-groove-bound. This is needed to compensate for the disruption of the A5-T16 Watson−Crick pairing (∼12 kcal/mol), the overall B-helix distortion, as well as a small penalty for BP dihedral compression of ∼7° (see Figure S6, Supporting Information). The mechanical constraint exerted by the flanking π-stacked DNA bases optimizes the π-stacking of BP within the B-helix. This beneficial effect is reinforced by HB stabilization of the ejected bases. Both are crucial for the viability of the double-inserted adduct that would otherwise be strongly penalized (see Figure S3, Supporting Information). This balance is reflected in the optimized interaction energy reaching −15.4 kcal/mol, a value that clearly denotes an attractive interaction and further ascertains the stable nature of the double insertion. It is slightly more stable than the minor groove binding value, in line with the known feature that the insertion mode is enthalpically driven whereas groove binding is entropically driven.18 From this energetic analysis, one can anticipate a close competition leading to a coexistence of the two modes, a usual feature for DNA−drug adducts. A definitive probe and straightforward assessment of the minor groove versus double insertion ratio is mostly of experimental resort and should rely on spectroscopic studies.19 To guide future studies, we have generated both UV/vis and CD spectra of the two stable DNA−BP adducts. This leads us to identify a most clear, highly specific CD signature for the double-inserted mode. Let us first discuss the opportunity of UV/vis-based detection. BP as a bicyclic, aromatic moiety presents an absorption spectrum featuring an intense absorption band in the near-UV region (∼270 nm), corresponding to π* ← π transitions, and a very weak absorption in the visible range (∼350 nm), assigned to weakly allowed π* ← n transitions. This reference experimental spectra20 are easily reproduced by theoretical calculations21 and also by our QM/MM MD simulation (see Figure S7-a, Supporting Information). The spectra that we calculated including an interaction with DNA, either along the minor groove or double-inserted trajectories (Figure S7-b, Supporting Information), are nearly identical. Hence, there is no ambiguity that UV/vis spectroscopy is inadequate to capture 4122



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and an eventually cooperative (weak) HB network that counterbalance the B-helix distortion. The importance of such HBs could be more general, especially in the case of neutral drugs that are not stabilized by the electrostatic interactions with the negatively charged DNA backbone. For this reason, we do no expect pronounced sequence dependence. We find that simulated CD spectra show with no ambiguity a very pronounced and intense negative band in the visible range for the double insertion. This spectroscopic signature can be exploited to experimentally discriminate this mode from the minor groove binding or even to assess for the different ratio. Parrallely, the stable structures obtained in this work will represent validated starting conformations for the forthcoming study of the energy-transfer process,30 relying on extensive dynamic studies including state hopping and spin coupling.

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COMPUTATIONAL SECTION

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ASSOCIATED CONTENT

S Supporting Information *

Details of the computational procedure and supplementary Figures S1−S12, including cartoon representations of the starting interaction structures, the time evolution of the most relevant distances describing the BP−DNA interaction, and UV−vis calculated spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (E.D.). *E-mail: [email protected] (A.M.). Notes

The authors declare no competing financial interest.

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REFERENCES

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To access the different interaction structures, we performed 20 ns classical MD trajectories on different starting adducts (intercalation, insertion, and minor and major groove binding, as recalled and discussed in the Supporting Information) using the Amber force field ff99 for DNA and gaff for the ligand.31 Details of the computational protocol can be found in the Supporting Information. Subsequent analysis has been performed using DFT on relaxed subfragments and topological tools such as the NCI analysis.32 Spectra have been obtained using time-dependent DFT (TDDFT) in our QM/MM scheme, taking into account mechanical, electrostatic, and polarization embedding.14 QM and QM/MM calculations, with a frontier placed on the deoxyribose−nucleobase linkage, have been performed with a local modified version of the Gaussian 09 code.33

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ACKNOWLEDGMENTS

This work was performed within the framework of the LABEX PRIMES (ANR-11-LABX-0063) of Université de Lyon, within the program “Investissements d’Avenir” (ANR-11-IDEX-0007) operated by the French National Research Agency (ANR). E.D. acknowledges the COST action CM1201 “Biomimetic Radical Chemistry”. A.M. thanks CNRS for funding the “chaire d’excellence” project. Calculations were performed using the local HPC resources of PSMN at ENS-Lyon and Université de Lorraine laboratories. 4123



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Benzophenone and DNA: Evidence for a Double Insertion Mode and

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