Effect of 8-Oxoguanine on DNA Structure and Deformability - The

Article pubs.acs.org/JPCB

Effect of 8‑Oxoguanine on DNA Structure and Deformability Tomás ̌ Dršata,† Mahmut Kara,‡ Martin Zacharias,‡ and Filip Lankaš*,† †

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo náměstı ́ 2, 166 10, Praha 6, Czech Republic ‡ Physik-Department (T38), Technische Universität München, James-Franck-Strasse 1, 85748 Garching, Germany S Supporting Information *

ABSTRACT: 8-Oxoguanine (oxoG) is an abundant product of oxidative DNA damage. It is removed by repair glycosylases, but exactly how the enzymes recognize oxoG in the large surplus of undamaged bases is not fully understood. The lesion may induce changes in the properties of naked DNA that facilitate the recognition. In this work, we assess the effect of oxoG on DNA structure and mechanical deformability. We performed extensive unrestrained, atomic resolution molecular dynamics simulations to parametrize a nonlocal, rigid base mechanical model of DNA. Our data indicate that oxoG induces unwinding of the base pair step at the 5′-side of the lesion. This brings the damaged DNA closer to its conformation in the initial complex with bacterial glycosylase MutM. The untwisting is partially caused by different BII substate populations and is further enhanced by the base−sugar repulsion within oxoG. On the other hand, our analysis shows that damaged and undamaged DNA have very similar harmonic stiffness. These results suggest an indirect readout component of the MutM−DNA initial complex formation. They also help one to understand the effect of oxoG on the formation of nucleosomes and looped gene regulatory complexes.

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INTRODUCTION Oxidative damage of nucleobases is an important source of mutations in DNA. In particular, the oxidation of guanine to 7,8-dihydro-8-oxoguanine (oxoG) is dangerous due to the capacity of oxoG to mispair with adenine in the process of replication, which results in G-C to T-A transversion mutations.1,2 To repair the damage, oxoG is removed by the glycosylase MutM (also known as Fpg) in bacteria3 and by its functional (but not structural) homologue Ogg1 in humans.4 The enzymes catalyze the base excision after extruding the nucleobase from the DNA helix and inserting it into the active site. Before the reaction can happen, the enzyme has to perform a formidable task of detecting an oxoG within a large surplus (ca. 106−107) of undamaged base pairs (bp). A series of crystallographic studies have shed light on the oxoG detection by the bacterial glycosylase MutM.3,5−7 To identify the oxoG lesion, MutM performs an initial interrogation of the DNA helix by intercalating one residue (Phe114) on the 3′-side of the inspected pair while all the bases are kept intrahelical. The inserted residue severely buckles the inspected pair and its 3′-neighbor, causes the two pairs to unstack, and induces a sharp bend of the DNA toward the major groove (roll ca. 45°−50°). As a result, the substituent at the 8-position of the target nucleobase is projected toward the backbone. If the base is oxoG rather than G, the big, negatively charged O8 clashes with the sugar moiety, causing it to pseudorotate to low pucker conformations (C4′-exo or C3′endo). At the same time, the base pair step between the target and its 5′-neighbor gets severely underwound. This alternative © 2013 American Chemical Society

conformation then lowers the activation barrier to break the damaged pair and extrude the target nucleobase out of the helix. The formation of the initial, intrahelical MutM−DNA recognition complex may be facilitated by changes in conformational properties of the naked DNA induced by the oxoG damage. In fact, many proteins recognize their DNA targets using specific conformation or stiffness of the DNA sequence, a mechanism called indirect readout.8,9 It is possible that the conformation of the DNA double helix or its deformability depends on the target base (G or oxoG) in such a way that the oxoG-containing complex is energetically preferred. Besides the repair complex formation, changes of DNA conformation or stiffness upon G to oxoG mutation may play a role in other functional contexts. For instance, they may affect the formation of nucleosomes or looped transctiption regulation complexes that largely depend on DNA-sequencespecific mechanical properties.10,11 The effect of G to oxoG mutation on the properties of naked DNA has been addressed by a number of studies. Crystallographic data suggest negligible conformational changes upon replacing G with oxoG in the double stranded DNA oligomer of an otherwise identical sequence.12−14 Other experiments indicate that oxoG alters the DNA hydration pattern and Received: July 30, 2013 Revised: September 10, 2013 Published: September 12, 2013 11617

dx.doi.org/10.1021/jp407562t | J. Phys. Chem. B 2013, 117, 11617−11622

The Journal of Physical Chemistry B

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force field21 was used, and the oxoG parameters were taken from the literature.23 The trajectories reported here were prolonged to 1 μs each. To analyze the MD data, we took snapshots in 10 ps intervals and processed them with the 3DNA software31 to obtain time series of conformational parameters. These include intra-basepair coordinates buckle, propeller, opening, shear, stretch, and stagger and inter-base-pair or step coordinates tilt, roll, twist, shift, slide, and rise, as well as backbone torsions and sugar puckers. During the simulations, the end base pairs had a tendency to break and the χ glycosidic torsions at the ends flipped to the syn conformation. Moreover, the base pairs in the whole oligomer occasionally broke and re-formed. These effects take place on a very long time scale and were not equilibrated within our simulation time. We thus decided to exclude them from the analysis. By filtering them out, we limit ourselves to the doublestranded conformations devoid of end breaks. Similar filtrations have been proposed earlier.32−34 The absence of broken ends mimics the biologically relevant limiting case of an oligomer embedded in a much longer DNA stretch. The filtered time series of intra-base-pair and step coordinates were used to parametrize a nonlocal, harmonic rigid base model of DNA shape and stiffness.27−30 In the model, DNA bases are represented as rigid bodies and the DNA conformation is fully described by a vector (w) of all the intra-base-pair and step coordinates. Notice that for a DNA double-stranded oligomer of n base pairs, w has 12n − 6 components. The deformation energy (or internal elastic energy) U of the model is assumed to take the general quadratic form

moderately destabilizes the damaged DNA.15−17 To our knowledge, no experimental data exist concerning the effect of oxoG on DNA stiffness. The various experimental methods provide valuable insight into the effect of oxoG on DNA properties. However, they also have limitations: the X-ray structures are static and may be affected by crystal packing forces, and other methods may not provide enough resolution to see the effects on an atomistic scale. Computational methods, in particular atomic-resolution molecular dynamics (MD) simulations with explicit inclusion of water and ions, may thus act as a useful complement.18,19 In MD simulations, one can follow the system dynamics in atomistic detail, which would be very difficult to achieve experimentally. The main limitations of MD are a simplified description of interatomic interactions (force field) and a rather short accessible time scale. A recent MD study used a modern DNA force field, long unrestrained MD trajectories, and advanced sampling methods to investigate the effect of G to oxoG mutation in a naked DNA oligomer.20 The authors report changes in DNA backbone torsions, sugar puckers, and hydration patterns upon the oxoG incorporation. The AMBER parmbsc0 force field21 used in that study corrects the spurious irreversible flips of the α/γ backbone torsions that polluted simulations with the old parm94/99 force fields and might have affected earlier, shorter oxoG simulations.22−25 Recently, an extensive MD study reported the free energy surfaces associated with the base extrusion.26 In the present work, we set out to comprehensively investigate the effect of oxoG on naked DNA structure and mechanical properties. Our results are based on microsecondlong, unrestrained, atomic-resolution MD simulations of a DNA oligomer containing either G or oxoG. Besides the backbone and sugar conformations, we study the effect of oxoG on the spatial arrangement of DNA bases as described by intraand inter-base-pair (or step) coordinates and on the mechanical stiffness associated with these coordinates. To this end we use our MD trajectories to parametrize a nonlocal harmonic model of DNA shape and stiffness where bases are modeled as rigid bodies.27−30 In this way, a rather complete picture of the effect of oxoG on DNA properties as predicted by modern MD simulations is obtained. The results are compared wherever possible to experimental structural data.

U (w) =

1 (w − ŵ ) ·K(w − ŵ ) 2

(1)

where ŵ is the vector of shape parameters defining the equilibrium conformation and K is a symmetric, positive definite matrix of stiffness parameters, or stiffness matrix. Thus, U is the energy cost of deforming the oligomer from its equilibrium conformation ŵ to the actual conformation w. Relations can be derived between the model parameters ŵ and K and ensemble averages of some simple functions of w. If the coordinate fluctuations are small, these relations take the form

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ŵ = ⟨w⟩,

METHODS The present trajectories are just prolongations of 200 ns unrestrained simulations reported in an earlier work,20 where details about the simulation setup can be found. Briefly, two palindromic, double stranded 10-bp DNA oligomers of the sequence CCAG*CGCTGG (where G* is either G or oxoG, Figure 1) were built as canonical B-DNA structures, immersed in water and sodium counterions, equilibrated, and simulated in NpT ensemble (T = 300 K, p = 1 atm). The AMBER parmbsc0

K = kBT C−1

(2)

Here ⟨ ⟩ denotes averaging over the canonical ensemble, T is the thermodynamic temperature of the ensemble, kB is the Boltzmann constant, and C is the covariance matrix of the coordinates w whose elements Cij are given by Cij = ⟨(wi − wî )(wj − ŵj)⟩

(3)

The model parameters were estimated by replacing the ensemble averages in eqs 2 and 3 by averages over the filtered MD time series. Only coordinates for the inner 8 bp part were used, yielding 90 coordinates in total. To compute eigenvalues and eigenvectors of the stiffness matrix, its entries have to be made dimensionally uniform. This is achieved by nondimensionalization using a length scale of 1 Å and an angle scale of 360/3.4 = 10.6°, motivated by canonical B-DNA conformation (twist 36° and rise 3.4 Å). A very similar scaling is implied by considering the dimension of individual base pairs.34

Figure 1. Base sequence of the studied oligomers. The damaged DNA (G* = oxoG in both strands) and the undamaged control (G* = G) were simulated. Naked DNA crystal structures with the same sequence, either containing G or oxoG, all show the same pattern of BI and BII backbone substates, here denoted by circles (empty circle, BI; filled circle, BII). 11618



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The correlation coefficient c between the Ap(oxoG) twist ω and the O8−O4′ distance d (Figure 6) was calculated as c=

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ApG* steps). This suggests that the crystal conformations may be to a large extent dictated by crystal packing forces and might not fully reflect the conformational differences upon G to oxoG mutation which take place in unconstrained, naked DNA in solution. Unwinding Is Partially Caused by Differences in BII Populations. There is an intimate connection between the conformation of a base-pair step and the BI or BII substates adopted by the two backbone fragments within that step.34−36 The substates are defined by the values of the backbone torsions ε and ζ (ε − ζ < 0 for BI and ε − ζ > 0 for BII; Figure 3). The two fragments within a step can be both in BI (the BI/

⟨(ω − ⟨ω⟩)(d − ⟨d⟩)⟩ ⟨(ω − ⟨ω⟩)2 ⟩⟨(d − ⟨d⟩)2 ⟩

(4)

RESULTS AND DISCUSSION oxoG Unwinds the 5′-Neighboring Step toward the Conformation in MutM−DNA Complex. The mean values of the intra-base-pair and step coordinates for the two simulated oligomers are shown in Figures 2 and S1 and S2

Figure 3. The BI and BII substates are defined by the backbone torsions ε (C4′−C3′−O3′−P) and ζ (C3′−O3′−P−O5′). The two torsions flip together in a crankshaft motion between the substate where ε − ζ < 0 (BI) and the one where ε − ζ > 0 (BII).

Figure 2. Average twist from MD simulations of damaged (G* = oxoG, red) and undamaged (G* = G, blue) DNA. Error bars indicate mean (unsigned) differences between the whole trajectory and its halves. The simulated Ap(oxoG) step is underwound by 7° compared to ApG and is thus closer to the conformation in the initial, intrahelical MutM−DNA recognition complex. This suggests an indirect readout component of the oxoG recognition by the enzyme. The crystal structures of the damaged (black) and undamaged (gray) oligomers all show almost identical twist profiles, presumably dictated to a large extent by crystal packing forces.

BI state) or both in BII (BII/BII) or one in BI and the other in BII (the BI/BII, or mixed state). It has long been known that these backbone states influence the step conformation: BI/BII implies higher twist, lower roll34−36 as well as higher slide34 than BI/BI. For the rare BII/BII the changes go in the same direction but are even more pronounced. The backbone fragments of the naked DNA crystal structures discussed above (1ENE, 1EN9, 1ZF5, and 183D) are all trapped in either BI or BII substate and exhibit the same pattern of BI and BII along the sequence, no matter whether it contains G or oxoG (Figure 1). Thus, the crystal structures cannot provide any information about the BI to BII equilibrium and its possible shifts caused by the oxoG lesion. To test whether the changes in twist upon G to oxoG mutation are caused by differences in BI to BII equilibrium, we computed the BII populations of the simulated oligomers (Figure 4). We observe that the BII substate is almost absent in

(Supporting Information). The symmetry features of the profiles required by the palindromic sequence and the small error bars indicate excellent convergence. The most dramatic effect of G to oxoG mutation is in the twist of the base-pair step at the 5′-side of the lesion (denoted generally by NpG* in this work). The twist of Ap(oxoG) is about 25°, while the twist of the corresponding undamaged ApG step is 32°. Thus, the presence of oxoG in place of G causes unwinding of the step at its 5′-side by roughly 7°. This conformational change makes the oxoG-containing naked DNA closer to the intrahelical MutM− DNA recognition complex. Indeed, the intrahelical MutM− DNA complexes exhibit an underwound NpG* step, with twist attaining 17° ± 2° for NpG and 22° ± 6° for Np(oxoG).6 Specifically for the 5′-sequence identical to the one studied here (N = A), it is 18° for ApG (PDB code 3U6O) and 26° (3U6C) or 16° (3U6Q) for Ap(oxoG).6 These results indicate that the oxoG-containing naked DNA is partially preformed, in terms of twist, to facilitate the creation of the MutM−DNA intrahelical recognition complex. It is informative to compare the MD values of the mean coordinates, and in particular of the twist, to the values from crystal structures of the same sequence. There are three highresolution (1 Å) crystal structures containing G (PDB codes 1ENE,13 1EN9,13 1ZF514) and one with oxoG (183D12), all with dyadic symmetry imposed by the crystal lattice. The X-ray values are shown together with the MD data for comparison (Figures 2 and S1 and S2, Supporting Information). It is seen that the twist values for both G and oxoG-containing crystals are actually very close to each other and may attain rather extreme levels (a twist of 50° for the CpA steps and 20° for the

Figure 4. BII backbone substate populations of the simulated oligomers. Since the sequence is palindromic, both strands (each taken in the 5′ to 3′ direction) are expected to show identical profiles. Our data for the reference strand (continuous lines) and complementary strand (broken lines) are indeed close to each other. The A-oxoG fragment has almost zero BII population, while the corresponding undamaged A-G has 25−30% of BII. This difference is partially responsible for the Ap(oxoG) unwinding. Error bars are computed as in Figure 2 11619



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the A-(oxoG) backbone fragment, while the BII population reaches 25−30% in the corresponding undamaged A-G fragment. This is reflected in the substates of the Ap(oxoG) step compared to ApG: the Ap(oxoG) is almost entirely in BI/ BI (99%); in contrast, ApG has only 71% of BI/BI but 29% of BI/BII (the BII/BII state is very rare in all steps). Thus, it is expected that Ap(oxoG) will exhibit lower twist just because it lacks the mixed BI/BII state, which, if present, increases twist. The mean twist computed separately for BI/BI and BI/BII states (Figure 5) shows that, indeed, the BI/BII twist is always

than for G (BI/BI, 3.07 Å for G and 3.42 Å for oxoG; BI/BII, 3.14 Å for G and 3.33 Å for oxoG). Moreover, the twist in Ap(oxoG) is negatively correlated with the distance d (correlation coefficient −0.42 for BI/BI and −0.28 for BI/ BII, computed using eq 4), whereas virtually no correlation is seen for G (−0.1 for BI/BI and +0.1 for BI/BII). These data suggest a likely additional cause of the Ap(oxoG) untwisting, apart from the effect of backbone substates: the oxoG base is pushed back toward lower twist by the intranucleoside O8− O4′ repulsion. The base−sugar interaction may also imply the observed differences of sugar puckers (Figures 7 and S3, Supporting

Figure 5. Average twist computed separately for substates where both backbone fragments in a given step are in BI (BI/BI) and where one fragment is in BI and the other in BII (BI/BII, or mixed). The third possible state (BII/BII) is very rare. Twist for BI/BII is always higher than for BI/BI. However, the unwinding of Ap(oxoG) compared to ApG is still apparent for each of the substates individually.

Figure 7. Average sugar puckers for the simulated oligomers. Profiles for the two strands (continuous and broken lines, respectively) should coincide due to the palindromic sequence, which the MD data satisfy very well. The pucker of oxoG is lower than that of G, bringing the damaged DNA closer to the initial MutM−DNA recognition complex.

Information). The oxoG pucker is lower than the pucker of G, in agreement with earlier findings.20 This change may again help in forming the MutM recognition complex on damaged DNA, although the lower pucker seen here for naked oxoG DNA (C1′-exo) is still rather far from puckers in the recognition complexes (C4′-exo or C3′-endo).6 The MD data further suggest a small (0.5 Å) increase in shift of the Ap(oxoG) step compared to ApG (Figure S1, Supporting Information). This difference likely does not play any role in the complex formation, since the two pairs in the ApG* step move together in the complex.6 All the other predicted differences are relatively small (Figures S1−S3, Supporting Information). The oxoG Lesion Does Not Alter DNA Stiffness. Besides the equilibrium conformation, the G to oxoG mutation may in principle also affect the mechanical stiffness of DNA. This would have far-reaching consequences not only for the formation of the repair complexes, but also in all other situations where DNA stiffness plays a role (indirect readout of DNA by proteins, formation of nucleosomes and looped regulatory complexes). This issue is all the more important given the difficulty in repairing oxoG within nucleosomes.37 To our knowledge, no experimental data on the effect of oxoG on DNA stiffness have been published. The coarse-grained, rigid base harmonic stiffness model used here only probes DNA stiffness within the realm of small deformations. Nevertheless, such deformations appear in nucleosomes and other protein−DNA complexes as well as in looped regulatory systems. We parametrize the model from the unrestrained MD simulations, using the relations between model parameters and moments of the coordinates (eqs 2 and 3). DNA sequence-dependent stiffness inferred from earlier unrestrained MD simulations using a simplified (local) version of the present model38,39 has proved useful, among other

higher than the BI/BI one. However, the figure also shows that Ap(oxoG) has a lower twist than ApG, even if the two substates are taken separately. Thus, besides the difference in BI/BII population, there must be an additional cause for the Ap(oxoG) untwisting. As we reported elsewhere,34 the BI/BII substates of a neighboring step affect the twist of the given step in certain cases. Here the 3′ neighboring G*pC step shows a pronounced difference in BII populations upon oxoG mutation, as found earlier,20 and is thus the primary suspect. However, we checked that the mean twist of ApG* is in fact not influenced by the substates of G*pC. Unwinding Correlates with the Base−Sugar Repulsion. The unwinding (decrease of twist) of the Ap(oxoG) step may be caused by repulsion between the bulky, negatively charged O8 atom of oxoG and its sugar O4′ atom. Since the same interaction also affects the BII population,20 we have to consider the BI and BII substates separately. We found that the distance d (Figure 6) between the position 8 atom (H8 in G and O8 in oxoG) and the sugar O4′ is always longer for oxoG

Figure 6. The oxoG nucleoside. The repulsion between the O8 atom of the base and the sugar O4′ atom (distance d) contributes to the decrease of twist in Ap(oxoG) compared to ApG. 11620



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things, in predicting protein−DNA affinity in a benchmark complex,40 promoter identification,41 effect of CpG methylation,42 nucleosome dynamics,43 or transition to continuum DNA models on longer scales.44 This adds confidence to the view that unrestrained MD can provide realistic data on sequence-dependent harmonic DNA stiffness. The rigid base model parameters reveal only very little difference in harmonic stiffness between the G- and oxoGcontaining DNA. Diagonal entries of the G and oxoG stiffness matrices (Figure 8) and the stiffness matrix eigenvalues (Figure Figure 10. Scalar products of eigenvectors of the stiffness matrices for the damaged (oxoG) and undamaged (G) DNA (left) and for the two halves of the G trajectory. Identical eigenvectors would imply ones (black) on the diagonal and zeros (white) elsewhere. Although the G vs oxoG eigenvectors show less similarity than those of the trajectory halves, they are close to each other.

lesion on the 5′-side becomes underwound upon G to oxoG mutation, an effect not seen in crystal structures, presumably due to packing forces. The twist decrease is related to different populations of BI and BII backbone substates and is further enhanced by the base−sugar repulsion within the oxoG nucleoside. The unwinding, as well as the lower pucker associated with oxoG, bring the damaged naked DNA closer to its conformation in the initial recognition complex with the repair enzyme MutM. This indicates an indirect readout component of the oxoG recognition by MutM. On the other hand, a nonlocal, harmonic rigid base model parametrized from our atomistic MD suggests that the damaged and undamaged DNA have essentially the same mechanical stiffness.

Figure 8. Selected diagonal stiffness constants of the nonlocal, harmonic rigid base model parametrized form our unrestrained MD simulations. Rather small differences are seen upon the G to oxoG mutation. The same is true for the other diagonal constants not shown in the figure.

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ASSOCIATED CONTENT

S Supporting Information *

Mean values of intra-base-pair and step coordinates, sugar puckers, major and minor groove widths. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Phone: +420 220 410 319. Fax: +420 220 410 320. E-mail: fi[email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by grant no. RVO61388963 provided by the Academy of Sciences of the Czech Republic (T.D. and F.L.). Financial support was further obtained from Deutsche Forschungsgemeinschaft (DFG) (SFB 749, project C5; M.K. and M.Z.). Supercomputer resources (M.K. and M.Z.) were provided by a PRACE-0 grant (project pr89tu).

Figure 9. Eigenvalues of the stiffness matrices. The initial part is magnified in the inset. The values for damaged (red) and undamaged (blue) DNA are very similar.

9) and eigenvectors (Figure 10) are in fact quite similar. Thus, our data suggest that there is a very small difference in DNA stiffness upon G to oxoG mutation. This, however, only applies to the case of small deformations (harmonic approximation) studied here. Differences may occur for large deformations, such as the unstacking of the G*pN step in the initial MutM− DNA recognition complex.6

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REFERENCES

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CONCLUSIONS In this work we studied the effect of G to oxoG mutation on the structure, substates, and mechanical deformability of naked DNA. To this end we performed microsecond-long, explicit solvent, atomic resolution unrestrained molecular dynamics (MD) simulations of a mutated and a control undamaged DNA oligomer. The simulations indicate that the step flanking the 11621



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Effect of 8-Oxoguanine on DNA Structure and Deformability - The

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