Structural, Dynamical, and Electronic Transport Properties of Modified

ARTICLE pubs.acs.org/JPCA

Structural, Dynamical, and Electronic Transport Properties of Modified DNA Duplexes Containing Size-Expanded Nucleobases Jose Ramon Blas,†,# Oscar Huertas,‡,# Carolina Tabares,§,# Bobby G. Sumpter,|| Miguel Fuentes-Cabrera,|| Modesto Orozco,^ Pablo Ordejon,*,§ and F. Javier Luque‡,* †

)

Departamento de Química Inorganica, Organica y Bioquímica, Facultad de Medicina, Universidad de Castilla-La Mancha, Avda. Almansa 14, Albacete, 02006, Spain ‡ Departament de Fisicoquímica and Institut de Biomedicina (IBUB), Facultat de Farmacia, Universitat de Barcelona, Avgda. Diagonal 643, Barcelona, 08028, Spain § Centre d’Investigaci o en Nanociencia i Nanotecnologia-CIN2 (CSIC-ICN), Campus UAB, 08193 Bellaterra, Spain Center for Nanophase Materials Sciences and Computer Science and Mathematics Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee, 37831-6494, USA ^ Molecular Modeling and Bioinformatics Unit, Institut de Recerca Biomedica, Barcelona Scientific Park, Josep Samitier 1-6, 08028 barcelona, Spain; Department of Life Sciences, Barcelona Supercomputing Centre, Jordi Girona 29, 08034 barcelona, Spain; Departament de Bioquímica, Facultat de Biologia, Universitat de Barcelona, Avgda Diagonal 647, Barcelona 08028, Spain

bS Supporting Information ABSTRACT: Among the distinct strategies proposed to expand the genetic alphabet, sizeexpanded nucleobases are promising for the development of modified DNA duplexes with improved biotechnological properties. In particular, duplexes built up by replacing canonical bases with the corresponding benzo-fused counterparts could be valuable as molecular nanowires. In this context, this study reports the results of classical molecular dynamics simulations carried out to examine the structural and dynamical features of size-expanded DNAs, including both hybrid duplexes containing mixed pairs of natural and benzo-fused bases (xDNA) and pure size-expanded (xxDNA) duplexes. Furthermore, the electronic structure of both natural and size-expanded duplexes is examined by means of density functional computations. The results confirm that the structural and flexibility properties of the canonical DNA are globally little affected by the presence of benzo-fused bases. The most relevant differences are found in the enhanced size of the grooves, and the reduction in the twist. However, the analysis also reveals subtle structural effects related to the nature and sequence of benzo-fused bases in the duplex. On the other hand, electronic structure calculations performed for xxDNAs confirm the reduction in the HOMOLUMO gap predicted from the analysis of the natural bases and their size-expanded counterparts, which suggests that pure size-expanded DNAs can be good conductors. A more complex situation is found for xDNAs, where fluctuations in the electrostatic interaction between base pairs exerts a decisive influence on the modulation of the energy gap.

’ INTRODUCTION The structural variability of DNA is relevant for the recognition with other biomolecular partners and the transfer of genetic information.14 The flexibility of DNA is dictated by a delicate balance of energetic contributions.57 Among those contributions, the hydrogen bonding between adenine (A) and thymine (T), and between guanine (G) and cytosine (C), proposed by Watson and Crick8 (WC) affords the linkage between the chemical structure of the four natural nucleic acid bases and the maintenance of the genetic code. The WC recognition pattern of physiological DNA could in principle be enlarged by resorting to unnatural nucleobase derivatives, which might expand the genetic alphabet and lead to new DNA duplexes with improved biotechnological properties.914 To this end, several strategies have been adopted, such as the use of non-natural hydrogen-bonding r 2011 American Chemical Society

patterns,1517 covalently linked base pairs,18,19 metal-mediated pairs,2023 or hydrophobic isosteres of the canonical bases.1427 Kool and co-workers have suggested a new strategy consisting of the use of size-expanded nucleobases, which pursue the increase of the hydrophobicity of the natural bases, while retaining their hydrogen-bond recognition properties. Three types of sizeexpanded bases, denoted as x- (Figure 1),2831 y-,3234 and yybases,35 have been proposed up to now. Both x- and y-bases are formed upon insertion (to A and G) or addition (to T and C) of a Special Issue: Pavel Hobza Festschrift Received: May 31, 2011 Revised: August 18, 2011 Published: September 02, 2011 11344

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Table 1. Duplexes Considered as Simulation Systems duplex 1

name DADT

sequence 50 -(A)14-30 30 -(T)14-50

2

DGDC

50 -(C)14-30 30 -(G)14-50

3

BABT

50 -(xA)14-30 30 -(xT)14-50 50 -(xC)14-30

4

BGBC

5

30 -(xG)14-50 DUP1 (xA-T) 50 - T-xA-xA- T-xA-xA- T-xA- T- T-xA- T- T-xA-30 30 -xA- T- T-xA- T- T-xA- T-xA-xA- T-xA-xA- T-50

Figure 1. Representation of benzo-fused expanded x-bases. 6

DUP2 (A-xT) 50 -xT- A- A-xT- A- A-xT- A-xT-xT- A-xT-xT- A-30 30 - A-xT-xT- A-xT-xT- A-xT- A- A-xT- A- A-xT-50

benzene ring to the natural DNA bases but differ in the positioning of six- and five-membered rings in benzo-fused purines. In turn, yy-bases consist of the fusion between a naphthalene ring and the natural base. As a result of these modifications, x- and y-bases are ∼2.4 Å wider than the natural counterparts, whereas yy-bases represent a geometrical displacement of about 4.8 Å. In the last years, several works have appeared on DNA base analogues that also led to duplexes of expanded size,3639 thus underscoring the interest of DNA widening strategies. Size-expanded bases have many properties that make them of biotechnological interest. Fully expanded DNAs composed of mixed pairs of natural bases and benzo-fused derivatives (xDNAs) exhibit a substantial stabilization of the helix with regard to the natural duplex, which can be attributed to the enhanced ππ stacking and hydrophobicity due to the large aromatic surface of x-bases.11,28,31,4042 Moreover, the preservation of the WC hydrogen-bonding scheme explains the similar sequence selectivity against mismatches found for both xDNA and DNA.43 A range of potential biotechnological applications has been suggested for x-bases, related always to their unique electronic structure. For example, they have been suggested as biomarkers for the detection of nucleic acid sequences, taking advantage of their fluorescence. Furthermore, because the HOMOLUMO gap of size-expanded bases is lower compared to that of their natural counterparts,4447 xDNAs can be used to build molecular nanowires.4851 Biotechnological possibilities of x-bases are increased by their ability to act as substrates of DNA polymerases, which might enable replication of xDNA.5255 Because the structural variability of base pairs has a direct impact on electronic processes in DNA duplexes,5658 knowledge of the structural and flexibility properties of size-expanded duplexes is necessary to explore their suitability as molecular nanowires. To the best of our knowledge, an exhaustive and systematic study of structural, dynamical, and electronic properties of modified DNAs with different levels of size expansion is still missing. This study reports the results of a wide and systematic molecular dynamics (MD) and density functional theory (DFT) analysis of the structural and dynamical features of size-expanded DNAs, which are examined in light of the properties determined for the corresponding natural duplexes. The studied systems span the path from nonsubstituted canonical DNAs to fully size-expanded duplexes (xxDNAs), through hybrid forms of intermediate width (xDNAs), thus enabling us to explore the progression of structural and dynamical properties in the process of DNA widening, as well as of the electronic structure of natural and modified duplexes.

7

DUP3 (xG-C) 50 - C-xG-xG- C-xG-xG- C-xG- C- C-xG- C- C-xG-30

8

DUP4 (G-xC) 50 -xC- G- G-xC- G- G-xC- G-xC-xC- G-xC-xC- G-30

30 -xG- C- C-xG- C- C-xG- C-xG-xG- C-xG-xG- C-50 30 - G-xC-xC- G-xC-xC- G-xC- G- G-xC- G- G-xC-50

’ METHODS Molecular Systems. To gain a consistent view about the structural and flexibility properties of modified DNAs containing x-bases, a series of 14-mer duplexes corresponding to the pure natural DNA and benzo-fused xx-DNA (i.e., each pair formed by two complementary x-bases) or the mixed x-DNA (i.e., each pair formed by a natural base and its complementary x-base) were considered (Table 1). Regarding the pure duplexes, poly(xA-xT) and poly(xG-xC) were chosen in conjunction with their corresponding canonical analogues poly(A-T) and poly(G-C). In the following these natural duplexes are denoted as DADT and DGDC, whereas the corresponding pure size-expanded duplexes are designated as BABT and BGBC. With regard to the x-DNA duplexes, four sequences that alternate base pairs formed by a natural base and the complementary benzo-fused nucleobase were chosen. The four xDNA duplexes (denoted as DUP14) share the same distribution pattern of base pairs (Table 1). It is worth noting that such a pattern was chosen because the central 10-mer region of DUP1 corresponds to the x-DNA duplex 50 (xATxAxATxATTxAT), which was characterized by NMR in aqueous solution.40 Accordingly, this choice facilitates a direct comparison between theoretical and NMR-derived structural properties. The rest of xDNA sequences were built up by replacing xA by A and T by xT (DUP2), or by performing the corresponding permutations with G, xG, C and xC bases (xA and T were replaced by xG and C in DUP3; A and xT were replaced by G and xC in DUP4; Table 1) Simulation Protocol. The structural and dynamical properties of the duplexes were examined from the analysis of the classical MD trajectories. In all cases, the starting structure of the 14-mer duplexes was built up using the geometrical parameters of a B-DNA duplex. They were immersed in a rectangular box (ranging from 24 48 98 to 28 51 98 Å3) containing between 3900 and 4800 water molecules and were neutralized by Na+ counterions. The model systems were then energy-minimized, thermalized (final temperature of 298 K), and preequilibrated using our well-established multistep protocol,59 with doubling the lengths of the windows to guarantee convergence. The production run extended for 10 ns using periodic boundary 11345

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conditions and particle mesh Ewald.60 SHAKE61 was used for hydrogen atoms in conjunction with an integration time step of 1 fs. The AMBER parmbsc0 force field62 and TIP3P63 water supplemented with specific parameters for benzo-fused bases derived using the RESP methodology and HF/6-31G(d) wave functions were used to represent molecular interactions (Table S1 in the Supporting Information). Snapshots were collected every picosecond for analysis. Simulations were done using AMBER9.0.64 Analysis of Trajectories. The structural analysis was performed considering the central 10 base-pair region of the duplexes and using in house software and standard codes like 3DNA65 and PTRAJ module of AMBER9.0, as well as in house software. The flexibility was examined using a variety of techniques comprising measurement of entropies determined by Andricioaei’s method66 coupled to the extrapolation scheme proposed by Harris et al.,67 essential dynamics,68 and harmonic stiffness analysis as suggested by Lankas and Olson.3,69,70 The essential dynamics of nucleic acids (normal or modified) was examined by diagonalization of the Cartesian covariance matrix C = C(ÆXiXjæ), which yielded to a set of eigenvectors (ν) and associated eigenvalues (λ). The former defines the nature of the essential deformation movement, and the second gives the amplitude, from which harmonic constants can be derived (eq 1). Ki ¼

kT λi

ð1Þ

where Ki is the force-constant associated with eigenvector νi. Finite-time pseudoharmonic entropies were determined by diagonalization of the mass-weighted covariance matrix obtained during the trajectory (eq 2). αi lnð1 eαi Þ ð2Þ S¼k αi 1 e i

∑

where αi = pωi/kT, ωi denotes the eigenvalues obtained upon diagonalization of the mass-weighted covariance matrix, k is Boltzmann’s constant, and the sum extends to all the nontrivial vibrations. Entropy estimates at infinite simulation time were obtained using Harris’ extrapolation technique (eq 3).67 α SðtÞ ¼ S∞ β ð3Þ t where α and β are fitted parameters and t is the simulation time used to obtain the entropy estimate. The stiffness of the base-pair steps was measured from the stiffness matrix F = F(Kij), which was derived by inversion of the covariance matrix defined in the helical reference system (eq 4). Diagonal elements in F represent deformation components due to pure helical variables, whereas off-diagonal terms account for coupling terms. F ¼ kTC1

ð4Þ

Finally, the similarity between different segments of the trajectories was determined using the γ index71 (eq 5), where the double sum is extended to the set (m) of most relevant essential deformation modes. γ¼

m

m

∑ ∑ jνj 3 νi j2 j¼1 i¼1

ð5Þ

The analysis of the structural and dynamical properties was performed using the snapshots taken every 1 ps in the last 3 ns.

Similar results were obtained for a time window covering the last 6 ns of the MD simulations (Supporting Information), which supports the structural integrity of the duplexes. Electronic Calculations. Electronic structure calculations were performed using the SIESTA program,72 which is a selfconsistent density functional theory method that uses pseudopotentials and a linear combination of numerical atomic orbitals as a basis set. Previously optimized double-ζ polarized bases were used for H, C, N, O, and P.73 The PBE74 functional (in the generalized gradient approximation) was used for the exchange correlation functional. Computations were performed for the central 10-mer segment of the sampled duplexes to avoid artifactual results due to the larger flexibility of terminal bases. The ending groups in the central 10-mer were saturated with hydrogen atoms.

’ RESULTS AND DISCUSSION Structural Properties. The structural integrity of the duplexes is supported by the time evolution of the positional root-mean square deviation (rmsd; computed using the average structure determined from the snapshots collected in the last 3 ns as reference), which is stable along the trajectory in all cases (Figure S1 in Supporting Information; see also Figure 2). The rmsd amounts to around 1.4 Å for canonical duplexes. Similar values are found for x-DNAs, but DUP3, as the rmsd amounts to 1.7 Å. Finally, a rmsd of 1.2 Å is found for the pure size-expanded duplexes BABT and BGBC. Sugar. As expected for natural duplexes, 20 -deoxyriboses mostly populate the south region (Table 2), it being slightly larger in DADT (91%) than in DGDC (85%), in agreement with previous studies that reported north conformers to be more populated in C than in T.7577 The preference for the south region is also found in BABT and BGBC, though there is a reduction in the south population (6166%). Finally, the puckering in xDNAs is intermediate between that observed for DNA and xxDNA duplexes: the largest south population is found for duplexes with benzo-fused purines, whereas xDNAs built up from benzo-pyrimidines are closer to pure xxDNAs. A feasible explanation is that the aromatic ring inserted in purines is relatively far from the sugar C10 atom compared to the case for benzo-fused pyrimidines. Finally, near all the bases exhibit fluctuations in the puckering, though the presence of north conformers varies transiently along the trajectories for north canonical and size-expanded bases. Compared to bonds for the canonical duplexes, the glycosidic bond (χ) deviates 1015 in xxDNAs (from 120.5 in DADT to 135.1 in BABT and from 130.8 in DGDC to 141.0 in BGBC). This effect is also found in mixed duplexes containing benzo-fused pyrimidines. However, xDNAs containing benzofused purines show the opposite tendency, as the average χ angle amounts to 104.8 and 121.7 for DUP1 (xA-T) and DUP3 (xG-C), respectively. In fact, when the conformational preferences are analyzed separately for benzopurines and benzopyrimidines (Tables S2 and S3, Supporting Information), one can realize that xA (DUP1) and xG (DUP3) populate χ angles around 120 and 70 (Figures S3 and S4, Supporting Information). As will be discussed below, the bimodal distribution of these bases also affects the values sampled for certain backbone dihedrals. Overall, benzo-fused bases do not introduce drastic changes in the sugar puckering and the glycosidic bond. This finding agrees with NMR data for xDNAs 50 (xATxAxATxATTxAT)40 and 11346



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Figure 2. Representative structures sampled in the molecular dynamics simulations for (top) DADT, BABT, DUP1, and DUP2 and (bottom) DGDC, BGBC, DUP3, and DUP4.

50 (xTGxTAxCxGCxAxGT),56 which support the anti conformation for the glycosidic bond and the south puckering of the deoxysugar. Backbone Dihedrals. The distribution of the backbone dihedral angles can be analyzed from the data shown in Table 2 (also Figure S2 and Tables S2S4 in the Supporting Information). Regarding the dihedral angle α, the average value is close to 70 for all the duplexes, but those containing benzo-fused purines (the average value amounts to 87 and 77 for DUP1 and DUP3, respectively). The dihedral angles β and γ are similar for all the duplexes, with average values close to 170 and 56 (Table 2). Only in BGBC and DUP3 is a marginal population of structure sample values close to 180 (Figure S2 in Supporting Information). The distribution of δ, ε, and ζ is more sensitive to the nature of the duplex. The dihedral angle δ in the canonical duplexes amounts to 120.8 (DADT) and 115.0 (DGDC). The inclusion of benzo-fused purines tends to increase the average value, though the reverse effect is found in duplexes containing benzofused pyrimidines and even in xxDNAs. The torsional angle ε mainly populates values close to 190, but there is a small fraction of structures sampling values close to 270. Notably, this latter

trend is especially relevant in duplexes DUP1 and DUP3. Similar trends are also found for ζ. The canonical duplexes mainly sample a value around 95, though there is a small fraction of structures with ζ values around 150. However, a more significant deviation is found for DUP1 and DUP3, where around 30% and 15% of the structures sample dihedral angles close to 110. The analysis of the conformational preferences for DUP1 and DUP3 reveals that xA and xG have a larger propensity to populate conformational regions characterized by ε and ζ close to (i) 190 and 270 or (ii) 270 and 120 (Figures S3 and S4, Supporting Information). Moreover, there is a correspondence between the bimodal distribution of χ found for benzopurines in DUP1 and DUP3 (see above) and the distribution of ε and ζ (Figures S3 and S4, Supporting Information). This trend is generally found in steps 50 -T-xA-30 (50 -C-xG-30 ) and likely reflects structural readjustments associated with the significantly larger overlap found between benzo-fused bases in those stacked base pairs in DUP1 and DUP3 compared to the natural duplexes or the pure size-expanded duplexes (Figure 3). In spite of the particular trends mentioned above, the conformational preferences of the backbone in duplexes with benzofused bases are globally similar to those found for canonical 11347



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Table 2. Average Values of Puckering, Backbone Dihedral Angles (Degrees), and Grooves Width for the Different Duplexesa DADT

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

Sugar south (%)

91

85

66

61

95

70

85

66

χ

120.5 (17.4)

130.8 (16.5)

135.1 (16.3)

141.0 (13.1)

104.8 (26.5)

130.8 (16.4)

121.7 (26.8)

135.8 (16.2)

α

68.6 (12.5)

70.3 (11.1)

68.5 (11.7)

68.9 (19.3)

86.7 (20.0)

69.4 (10.8)

76.7 (30.4)

70.2 (11.6)

β

170.2 (13.5)

173.3 (11.5)

170.6 (9.7)

171.6 (9.2)

167.4 (13.1)

172.1 (10.2)

170.8 (15.0)

172.3 (10.2)

γ

56.1 (9.9)

56.0 (9.6)

57.5 (9.2)

58.9 (14.5)

54.4 (10.8)

57.1 (9.0)

56.3 (23.0)

57.7 (9.3)

δ

120.8 (18.5)

115.0 (19.3)

102.4 (18.1)

99.6 (16.3)

131.2 (16.0)

107.5 (21.0)

119.1 (21.1)

107.0 (21.8)

ε ζ

170.6 (25.8) 96.4 (33.7)

171.5 (15.3) 91.9 (20.5)

172.2 (14.0) 87.0 (19.8)

171.8 (10.4) 85.3 (13.1)

141.5 (42.9) 95.6 (75.0)

173.1 (10.9) 87.9 (14.3)

157.8 (36.9) 92.6 (56.4)

171.9 (12.9) 87.9 (16.1)

minor (Å)

10.9 (1.3)

13.8 (1.2)

15.9 (1.2)

16.4 (1.2)

12.9 (2.0)

14.4 (1.1)

14.7 (2.0)

14.6 (1.0)

major (Å)

19.8 (2.2)

20.5 (2.4)

25.8 (2.4)

27.9 (2.3)

21.5 (3.0)

21.7 (2.9)

22.5 (3.2)

22.9 (2.4)

Backbone

Grooves

a

Dispersion is measured as standard deviation.

Figure 3. Representative structures of the stacked base pairs in (A) the natural duplex DADT (50 T-A30 ), (B) pure size-expanded BABT (50 xTxA30 ), and hybrid duplexes (C) DUP1 (50 T-xA30 ) and (D) DUP2 (50 xT-A30 ).

DNAs (Figure 2), which agrees with the large resemblance found between the average helical structure derived from NMR data and the helical structure of the canonical DNA duplex.40,78 Overall, these findings reflect the plasticity of the helix to accommodate size-expanded bases without drastic alterations in the backbone. Grooves. Minor and major grooves in DNA duplexes are sequence-dependent, as noted in average values of 10.9 and 19.8 Å for DADT, and 13.8 and 20.5 Å for DGDC (Table 2). As expected, benzo-fused bases increase the size of grooves (Figure 2), though such an increase is also sequence-dependent. Thus, the minor groove is enlarged 5.0 Å for BABT, but only 2.6 Å for BGBC. Conversely, the major groove increases 6.0 and 7.4 Å for BABT and BGBC, respectively. As a result, whereas major and minor grooves differ by 6.78.9 Å in natural DNAs, this difference increases to 9.911.5 Å in xxDNAs. Though the grooves in mixed xDNAs are comprised between those determined for natural DNAs and xxDNAs, their plasticity is reflected in the average values obtained for the four duplexes, ranging from

12.9 to 14.7 Å for the minor groove and from 21.5 to 22.9 Å for the major groove (Table 2). Thus, insertion of benzo-bases leads to major changes in groove dimensions, which might affect the ability to interact with small groove binders and DNA-binding proteins. Base Pairs. Inspection of the base-pair helical parameters (Table 3) shows that modified duplexes retain many properties of canonical DNAs. Remarkably, comparison of pure DNAs and xxDNAs reveals a slight reduction in rise (by 0.10.2 Å) and the tendency to minimize the sequence-sensitivity in slide and roll. However, the major difference between modified and natural DNA affects twist, which is reduced by around 8 in pure xxDNAs compared to that in natural duplexes, leading in turn to a larger number of base pairs per helix turn (around 1516 in xxDNA versus 1112 in DNA). Mixed xDNAs exhibit an intermediate character, as noted in a rise of 3.4 Å and a twist ranging from 25 to 28, which implies around 13 base pairs per turn. These findings are in excellent agreement with the average NMR-derived structure determined for both 50 (xATxAxATxATTxAT)40 and 50 (xTGxTAxCxGCxAxGT),78 where the twist was decreased by around 6 compared to that in the canonical B-DNA, leading to an average number of base pairs per turn close to 12. As noted by Liu et al.,40 the reduced twist contributes to relieve the conformational stress due to the larger size of benzobases, whose accommodation is also facilitated by small conformational adjustments in the backbone (see above). Our simulations also support the slight reduction in rise determined experimentally for 50 (xATxAxATxATTxAT) and argue against the sizable increase in rise (up to 4.0 Å) reported for 50 (xTGxTAxCxGCxAxGT).78 The parameters that define the internal geometry of bases in the base pair are generally similar in the different duplexes (Table 4). The most apparent change is found in stretch, which is enlarged by around 2.3 and 4.3 Å for xDNAs and xxDNAS, respectively, compared to the stretch for natural duplexes, thus reflecting the insertion of one (xDNA) or two (xxDNA) benzene units in the base pair. However, other fine details of the duplexes reflect more subtle effects. For instance, opening of bases is less favored in BABT compared to DADT, though this effect is not apparent in mixed xDNAs (DUP1 and DUP2). In contrast, the 11348



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Table 3. Average Values of Base-Pair Helical Parameters (Shift, Slide, and Rise in Å; Tilt, Roll, and Twist in Degrees) in Duplexesa DADT

a

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

shift

0.1 (0.1)

0.0 (0.2)

0.1 (0.2)

0.0 (0.1)

0.0 (0.1)

0.0 (0.2)

0.0 (0.2)

0.0 (0.2)

slide

1.1 (0.3)

1.8 (0.2)

1.8 (0.2)

2.1 (0.2)

0.5 (0.4)

1.5 (0.3)

1.2 (0.3)

1.8 (0.2)

rise

3.4 (0.1)

3.5 (0.1)

3.3 (0.1)

3.3 (0.1)

3.4 (0.1)

3.4 (0.1)

3.4 (0.1)

3.4 (0.1)

tilt

1.4 (1.1)

0.1 (1.1)

1.5 (1.1)

0.5 (0.9)

0.5 (0.9)

0.0 (1.2)

0.1 (1.0)

0.1 (1.2)

roll

1.1 (2.2)

4.0 (1.9)

3.2 (1.5)

3.8 (1.8)

2.8 (1.6)

5.4 (1.9)

4.7 (2.0)

3.3 (1.9)

twist

33.2 (1.0)

30.0 (1.1)

24.7 (1.1)

22.9 (0.8)

26.3 (1.8)

27.4 (1.0)

25.3 (1.6)

27.4 (0.9)

Standard deviations are indicated in brackets.

Table 4. Average Values for Different Base Translational (Å) and Rotational (Degrees) Parameters of the Different Duplexesa DADT

a

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

shear

0.2 (0.1)

0.0 (0.1)

0.5 (0.2)

0.6 (0.2)

0.1 (0.2)

0.0 (0.2)

0.0 (0.2)

stretch

0.2 (0.1)

0.1 (0.1)

4.4 (0.1)

4.2 (0.2)

2.4 (0.1)

2.3 (0.1)

2.4 (0.1)

2.1 (0.1)

stagger buckle

0.2 (0.2) 6.2 (4.8)

0.3 (0.1) 2.0 (3.2)

0.6 (0.6) 8.1 (4.0)

1.2 (0.6) 0.5 (3.0)

0.2 (0.3) 2.0 (3.9)

0.5 (0.3) 0.1 (3.7)

0.4 (0.3) 1.7 (3.8)

0.6 (0.3) 0.1 (3.3) 6.0 (4.7)

0.0 (0.2)

propeller

15.3 (3.9)

0.8 (3.9)

16.8 (4.6)

8.9 (4.4)

17.1 (3.8)

10.5 (5.3)

7.0 (4.1)

opening

4.3 (2.3)

0.2 (1.6)

0.2 (2.6)

0.9 (1.8)

3.9 (2.6)

4.2 (2.4)

0.2 (1.9)

0.2 (1.7)

X-displacement

1.0 (0.4)

2.2 (0.8)

2.1 (0.9)

2.6 (1.1)

0.0 (0.3)

2.0 (0.7)

0.7 (0.6)

2.3 (0.7)

Y-displacement

0.2 (0.3)

0.1 (0.5)

0.3 (0.7)

0.1 (1.0)

0.1 (0.6)

0.0 (1.1)

0.1 (0.7)

0.0 (1.0)

inclination

5.7 (5.1)

5.8 (5.1)

11.8 (6.7)

14.3 (7.8)

7.0 (5.8)

6.1 (7.3)

10.9 (5.9)

7.9 (5.2)

tip

0.8 (2.8)

0.7 (3.6)

0.6 (4.6)

0.8 (5.1)

0.2 (4.8)

0.5 (6.6)

0.6 (5.1)

0.2 (6.2)

Standard deviations are indicated in brackets.

Table 5. Force Constants of Intra- and Inter-Base-Pair Parametersa intra base pair

a

DADT

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

shear stretch

4.084 23.766

3.714 31.289

2.235 16.185

2.166 16.401

3.115 26.593

2.733 16.072

2.480 25.260

2.949 27.524

stagger

2.818

3.635

1.537

1.755

3.370

2.080

3.085

2.535

buckle

0.005

0.006

0.011

0.013

0.011

0.006

0.009

0.008

propeller

0.004

0.005

0.005

0.006

0.007

0.004

0.005

0.005

opening

0.022

0.081

0.039

0.062

0.017

0.031

0.031

0.086

inter base pair

DADT

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

shift

1.912

1.426

2.073

1.752

2.289

1.227

1.258

1.787

slide rise

2.626 4.651

3.020 4.580

4.498 8.208

4.976 8.183

3.302 9.875

3.063 6.509

1.868 7.249

4.007 6.948

tilt

0.022

0.023

0.037

0.041

0.039

0.016

0.031

0.018

roll

0.011

0.010

0.014

0.014

0.020

0.012

0.011

0.011

twist

0.034

0.039

0.061

0.061

0.049

0.051

0.036

0.053

Translational values are in kcal mol1 Å2, and rotational ones are in kcal mol1 deg2.

buckle of bases detected in homoduplexes DADT and BABT is smaller in heteroduplexes DUP1 and DUP2. Taking advantage of the normal distribution of helical parameters, stiffness analysis can be used to determine the rigidity of the different steps to distortions along helical coordinates (Table 5). Regarding the intra-base parameters, there is generally little difference between the stiffness constants determined for buckle, propeller twist, and opening for the different duplexes. Pure xxDNAs are slightly softer than canonical duplexes regarding shear, stretch, and stagger. Hybrid duplexes appear to adopt intermediate values between those found for pure DNAs and xxDNAs.

With regard to inter-base parameters, pure xxDNAs exhibit larger translational and rotational rigidity. This is especially noteworthy in the case of rise, as the stiffness constant increases from around 4.6 (in DNA) to 8.2 (in xxDNA) kcal mol1 Å2, and in twist, where the constant varies from 0.035 (in DNA) to 0.060 (in xxDNA) kcal mol1 deg2 (Table 5). In general, hybrid duplexes possess intermediate stiffness constants, though the data in Table 5 clearly indicate that there is some degree of variability depending on the nature of the benzo-fused base. Overall, the results suggest that insertion of benzo-fused bases should yield to a slight increase in the stiffness of the base pairs, as expected from the large stabilization of the stacking interactions, 11349



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Table 6. Similarity Values between the Set of 10 Most Relevant Essential Motions Determined for the Different Duplexes

DADT DGDC BABT BGBC

DADT

DGDC

BABT

BGBC

DUP1 (xA-T)

DUP2 (A-xT)

DUP3 (xG-C)

DUP4 (G-xC)

0.76

0.62

0.64

0.60

0.60

0.63

0.60

0.65

0.84

0.68

0.74

0.65

0.77

0.65

0.76

0.87

0.82

0.64

0.77

0.68

0.78

0.95

DUP1 (xA-T)

0.70

0.83

0.73

0.81

0.86

0.66

0.75

0.63

DUP2 (A-xT)

0.94

DUP3 (xG-C) DUP4 (G-xC)

even though the magnitude of this effect depends on the specific content and sequence of benzo-fused bases in the duplex. Global Deformability. The flexibility of the duplexes was examined by using the essential motions determined for the backbone atoms (total amount of 220 atoms) of the duplexes to avoid noise related to the movement of the base pairs. Inspection of both the first five and ten normal modes reveal that they account for a larger structural variance in the case of pure xxDNAs than in the canonical ones (Table S5 in the Supporting Information). Likewise, the entropies calculated for xxDNAs (around 1.20 and 1.18 kcal/mol for BABT and BGBC, respectively) are smaller than those determined for the canonical duplexes (around 1.25 and 1.28 kcal/mol for DADT and DGDC, respectively), indicating a lower global flexibility for the pure benzo-fused duplexes, which agrees with the stiffness analysis presented above. Regarding xDNAs, those containing benzofused purines (DUP1 and DUP3) exhibit configurational entropies larger than those formed by benzo-fused pyrimidines (Table S5, Supporting Information), also in agreement with stiffness analysis. The similarity between global deformations of the duplexes has been determined from the comparison of the essential motions extracted from the 710 ns time window, and selfsimilarities have been calculated by comparison between the normal modes obtained from 4 to 7 ns and 7 to 10 ns (Table 6). Self-similarities in pure xxDNAs (0.87 and 0.95 for BABT and BGBC) are larger than those determined for pure canonical duplexes (0.76 and 0.84 for DADT and DGDC). This finding likely reflects the reduced conformational flexibility due to increased rigidity of xxDNAs compared to that of the canonical duplexes. Cross-similarities range from 0.60 to 0.74, which indicates a significant correspondence in the global deformability between pure canonical and pure benzo-fused bases. The flexibility pattern of hybrid duplexes is slightly more similar to that of xxDNAs (similarity indexes from 0.64 to 0.81) than to natural DNAs (similarity indexes from 0.60 to 0.77). Energy States and Gaps in the Duplexes. To explore the electronic structure in the different duplexes, DFT-PBE computations were performed to analyze the molecular frontier orbitals, and to relate the gap and levels of individual bases and base pairs with the total gap and molecular orbitals of the duplexes. In addition, it is worth analyzing the influence of the differences in structural features for the interaction between base pairs on the nature of the gap in the duplexes. The contribution of the bases to the frontier orbitals was first analyzed for samples of 10 different snapshots taken during the last part of the trajectory for every duplex. As expected for pure canonical and benzo-fused duplexes, the HOMO orbital is located over the strand formed with bases with the highest HOMO (A, xA, G, xG), and the LUMO orbital over the strand

0.71

0.85

0.80

0.67 0.95

with bases of lower LUMO (T, xT, C, xC). However, for hybrid duplexes frontier orbitals are located over both natural and benzo-fused derivatives. Then, the energy levels of such frontier orbitals and the corresponding gaps were calculated for 100 structures of each duplex, taken at intervals of 50 ps within the last 5 ns of the trajectories. With the introduction of benzene in the duplexes, the HOMO is expected to go up due to (i) an upward shift of the HOMO of benzo-fused bases and (ii) its broadening resulting from the interaction with the HOMOs of the other base pairs. Likewise, the LUMO is expected to have a similar trend in opposite direction (a lowering of the state). Thus, the resulting gap is expected to decrease with respect to the canonical duplexes. The results in Figure 4 confirm that the gap diminishes with the introduction of the benzene unit in going from pure canonical to pure benzo-fused duplexes, which arises from an upward shift of the HOMO by 0.13 and 0.04 eV in BABT and BGBC, whereas the LUMO is shifted ca. 0.4 eV downward in both BABT and BGBC compared to the canonical duplexes (Table 7). This trend mimics the changes observed in the isolated bases, as the HOMO rises by 0.26 and 0.18 eV upon benzene insertion in A and G, whereas the LUMO of T and C is lowered by 0.26 and 0.43 eV upon conversion to xT and xC (Table S6 in Supporting Information). The changes in the gap determined for hybrid duplexes, compared to those for the regular DADT and DGDC duplexes, are more complex (Table 7) and cannot be interpreted solely in terms of the introduction of the benzene rings, because differences in the sequence of the bases influences the position of the frontier orbitals.79,80 In DUP1 (xA-T) the gap is reduced by 0.28 eV due to the shift up in the HOMO by 0.25 eV, which agrees with the change determined for the isolated base (0.26 eV for the change from A to xA), whereas the LUMO is nearly unaltered (2.35 in DADT and 2.38 eV in DUP1). In contrast, there is no relevant change in the gap for DUP2 (A-xT), as the lowering (by 0.40 eV) in the LUMO due to the replacement of T by xT is counterbalanced by the shift down in the HOMO (from 4.53 eV in DADT to 4.94 eV in DUP2). For DUP3 (xG-C) and DUP4 (G-xC), the gap is even larger than that found for the pure canonical duplexes. In DUP3 the increase (by ca. 0.8 eV) in the gap is mainly due to the shift up in the LUMO (from 2.92 eV in DGDC to 2.31 eV in DUP3). Moreover, the HOMO is slightly shifted down (from 3.64 eV in DGDC to 3.80 eV in DUP3), which is in contrast with the change determined for the HOMO of the isolated (G and xG) bases. For DUP4 the increase (by ca. 0.7 eV) in the gap mainly reflects the shift down of the HOMO (from 3.64 in DGDC to 4.20 in DUP4), whereas the LUMO remains largely unaffected, in contrast with the lowering of the LUMO measured for the isolated (C and xC) bases. 11350



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Figure 4. Evolution of the energy levels of HOMO and LUMO in the molecular dynamics calculation for (top) DADT, BABT, DUP1, and DUP2 and (bottom) DGDC, BGBC, DUP3, and DUP4.

Table 7. HOMO and LUMO Levels (eV) for DNA Duplexes (Averaged over 100 Structures)a duplex

HOMO

LUMO

gap

DADT

4.53

2.35

2.18

BABT

4.40

2.72

1.68 (0.50)

DUP1 (xA-T) DUP2 (A-xT)

4.28 4.94

2.38 2.75

1.90 (0.28) 2.19 (+0.01)

DGDC

3.64

2.92

0.72

BGBC

3.60

3.34

0.24 (0.48)

DUP3 (xG-C)

3.80

2.31

1.49 (+0.77)

DUP4 (G-xC)

4.20

2.88

1.38 (+0.66)

a

In some representative cases, differences against reference canonical duplexes are given in brackets.

Overall, these findings suggest that the relative location of the frontier orbitals within the duplexes must be affected by other parameters besides broadening and shifting of the bases at molecular levels. In particular, it is speculated that fluctuations in the electrostatic interaction between base pairs due to the dipoles of the bases and base pairs would result in an additional shifting of the levels.81 More specifically, the sequence of base pairs affects the relative direction of dipole moments between successive bases, leading to a change in the local electrostatic potential and consequently the onsite energies of the frontier orbitals of the corresponding bases. The electric dipoles in A (1.02 D) and T (1.89 D) are considerably smaller than those in G and C (2.69 and 2.73 D, respectively). Insertion of benzene in A increases the dipole by ca. 40%, whereas there is a reduction (by ca. 10%) in the dipole upon

insertion in G. For pyrimidines, addition of benzene increases the dipole in T and C by around 10% and 7%, respectively. Formation of dimers for A, T, xA, and xT leads to a significant dipole annihilation (electric dipoles of 0.75, 0.69, 0.48, and 0.93 au for A-T, xA-xT, xA-T, and A-xT), and the net dipole largely deviates from the main axis of the base pair pointing toward the pyridimidine base (Figure S5, Supporting Information). Accordingly, it is not surprising that the frontier orbitals in the dimer remain little affected by hydrogen bonding of the bases (Table S6, Supporting Information). In contrast, dimerization of G, xG, C, and xC gives rise to complexes with a large electric dipole (2.22, 1.96, 1.98, and 2.18 au for G-C, xG-xC, xG-C, and G-xC; Figure S5, Supporting Information), and the net dipole is aligned along the main axis of the base pair. As a result, the electronic states on G are shifted up in energy and those of C are shifted down (Table S6, Supporting Information). With these results in mind, we tested the proposal that differences in the local electric potential of the base pairs are to a large extent responsible for the shifts in hybrid duplexes. Accordingly, we determined the frontier orbitals for different sequences (parallel, purine 3 purine; antiparallel, purine 3 pirimidine) of two stacked (canonical-benzo-fused) base pairs extracted from the MD trajectories run for hybrid duplexes (DUP14). Two series of calculations were done, one including the backbone (phosphates and sugars) and the other one without it (Table 8). As expected, the differences in the states between parallel and antiparallel sequences are higher for G and C-derived base pairs. The presence of the backbone does not affect the relative position of the levels and their shifting upon stacking modes; therefore, the effect analyzed can also be considered for an entire DNA chain. Parallel stacking gives rise to higher HOMOs and lower 11351



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Table 8. HOMO and LUMO Levels (eV) for Stacked Base Pairs with Parallel (Purine 3 Purine) and Antiparallel (Purine 3 Pirimidine) Sequence without sugar and phosphates

Table 9. Energy Gap in Canonical Base Pairs Having Twist, Rise, and Slide Parameters Corresponding to the Modified Base Pairs

with sugar and phosphates

Modified parameter

base pair

HOMO

LUMO

gap

HOMO

LUMO

gap

base pair

none

twist

rise

slide

A-xT

4.97

2.58

2.39

4.90

2.53

2.37

A-T

2.39

2.25

2.29

2.32

G-C

1.35

1.25

1.26

1.31

A-xT 5.15

2.33

2.82

5.12

2.33

2.79

xA-T xA-T

4.49

2.33

2.16

4.13

2.34

1.79

xA-T

4.58

2.30

2.28

4.26

2.02

2.24

4.03

3.09

0.94

4.08

3.09

0.99

4.25

2.29

1.96

4.38

2.29

2.09

xG-C xG-C

3.79

2.72

1.07

3.57

2.50

1.07

xG-C

4.12

2.27

1.85

3.95

2.12

1.83

A-xT xT-A

T-xA G-xC G-xC G-xC xC-G

C-xG

LUMOs than antiparallel stacking, in agreement with previous results.81,82 In a parallel configuration the base determining the HOMO (G, A) interacts with the same base, which has a positive potential (higher electronic density) and, therefore, the HOMO shifts up, whereas the base determining the LUMO (C, T) interacts with the same base, which has a negative potential (lower electronic density) and, thus, the LUMO shifts down. In the antiparallel configuration, the base determining the HOMO interacts with the opposite base, which has a negative potential (lower electronic density), and the HOMO is shifted down. The base determining the LUMO interacts with the base having a positive potential (higher electronic density); therefore, the LUMO is shifted up. In the mixed duplexes examined here, there are not three base pairs in a parallel configuration. Therefore, this shifting dipole effect will lower HOMOs and raise LUMOs compared to the fully parallel sequences, then leading to a larger gap for mixed sequences even upon insertion of the benzene ring. The exception of DUP1, where the frontier orbitals have practically the same energy with the corresponding pure sequences, arises from a dipole interaction such that the shifting brings the HOMO’s and LUMO’s from both xA and T to similar energies; therefore, the HOMO of the duplex can remain high with the T HOMO even if the HOMO of xA would tend to go down due to dipole interaction, and the LUMO can stay low despite T LUMO going up thanks to the lowering of xA LUMO. A final remark on the molecular states is that all states in the HOMO and LUMO bands are strongly localized, both in the pure and in hybrid duplexes, as described previously in the literature.56,73,79,81 In the former case, this is due to the structural distortions during the dynamics, which yields to electronic Anderson localization82 in 1 dimension.56,79 For the hybrid complexes, besides the disorder induced by the dynamical structural distortions, there is the additional effect of the disruption of the π-stacking, and the effect of the changes in electrostatic potential with different stacking modes.73,79 These results

stress the importance of onsite energies in the electronic and transport properties of DNA.8385 Structural Effects in Electronic Structure. Because an efficient stacking will affect both coupling and dipole interaction, a last series of calculations were conducted looking for the relevance that changes on structural parameters have on the gap. Among the structutral parameters characterizing a DNA helix, the most affected with the introduction of the benzene moiety are twist, rise, and at less extent slide (Table 3). Accordingly, base pairs were extracted from DADT and DGDC duplexes, and their geometry was modified to have the twist, rise, slide parameters of BABT and BGBC: a lower twist angle, a lower rise and a higher slide. The results (Table 9) show that the differences local helical parameters do not lead to significant changes in the gap value and accordingly conductor properties of modified nucleobases are rather robust to local geometrical changes.

’ CONCLUSIONS The structural analysis performed for the different size-expanded duplexes reveals that, quite surprisingly, not only the structural but also the deformability properties of the canonical DNA are not dramatically affected by the presence of benzofused bases. The most relevant differences are found in the size of the grooves, which reflect the insertion of one or two benzene rings in xDNA and xxDNA, respectively, and the reduction in the twist, which facilitates the insertion of the size-expanded bases and contributes to eliminate conformational stress in the phosphodiester backbone. Modified nucleic acids are more rigid than parent DNAs, but the patterns of essential deformability are very similar. Overall, these findings reflect the significant plasticity of the helix to accommodate the size-expanded bases without a drastic alteration in the conformational preferences of the backbone. Our results also reveal the occurrence of sequencedependent effects, such as the decrease of South puckering associated with benzopyrimidines, and the slight changes in the distribution of certain backbone angles for benzopurines in hybrid xDNAs. The electronic structure calculations performed for xxDNA reveals the changes in the energy levels and the reduction in the gap predicted from the analysis of the natural bases and their size-expanded counterparts. Notably, the lowest gap is achieved for the regular parallel sequence of BGBC (xG-xC) base pairs, which leads to a sizable reduction in the gap compared to that of the corresponding natural duplex. A similar trend is also observed for BABT. Nevertheless, the analysis of the results determined for hybrid duplexes reveal that, besides the intrinsic shifting of the frontier orbitals due to insertion of benzene, fluctuations in the electrostatic interaction between base pairs exerts a decisive influence on the modulation of the energy gap. Therefore, the specific sequence of size-expanded bases is 11352


The Journal of Physical Chemistry A decisive for the electronic and transport properties of in modified DNA duplexes.

’ ASSOCIATED CONTENT

bS

Supporting Information. Time evolution of rmsd profiles, distribution of backbone angles, average values of backbone dihedrals, force field parameters, partial charges, structural variance for the first normal modes, dipoles of mixed base pairs, and energy of frontier orbitals for canonical and modified bases. This material is available free of charge via the Internet at http:// pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: F.J.L., [email protected]; P.O., [email protected]. Author Contributions #

These authors contributed equally to this work

’ ACKNOWLEDGMENT Dr. A. Perez is kindly acknowledged for valuable discussions. F.J.L., M.O., and P.O. acknowledge the financial support received from the Spanish Ministerio de Ciencia e Innovacion (SAF200805595, BIO2009-10964, CONSOLIDER CSD2007-00050 “Supercomputing and e-Science”, and FIS2009-12721-C04-01) and the computational facilities from the Centre de Supercomputacio de Catalunya (CESCA). P.O. aknowledges the access to the computational facilites of the Centro de Supercomputacion de Galicia (CESGA). O.H. and C.T. were supported by fellowships from the Spanish Ministerio de Ciencia e Innovacion. J.R.B. benefits from a postdoctoral grant of the Consejería de Educacion, Ciencia y Cultura of the Junta de Comunidades de Castilla La Mancha and the European Social Fund. Part of this research was conducted at the Center for Nanophase Materials Sciences, which is sponsored at Oak Ridge National Laboratory by the Office of Basic Energy Sciences, U.S. Department of Energy. ’ REFERENCES (1) Perez, A.; Lankas, F.; Luque, F. J.; Orozco, M. Nucleic Acids Res. 2008, 36, 2379. (2) Ditzler, M. A.; Otyepka, M.; Sponer, J.; Walter, N. G. Acc. Chem. Res. 2010, 43, 40–7. (3) Orozco, M.; Noy, A.; Perez, A. Curr. Opin. Struct. Biol. 2008, 18, 185–193. (4) Laughton, C. A.; Harris, S. A. WIREs Comput. Mol. Sci. 2011 in press. (5) Hobza, P.; Sponer, J. Chem. Rev. 1999, 99, 3247. (6) Hobza, P.; Sponer, J. J. Am. Chem. Soc. 2002, 124, 11802. (7) Sponer, J.; Jurecka, P.; Hobza, P. J. Am. Chem. Soc. 2004, 126, 10142. (8) Watson, J. D.; Crick, F. H. C. Nature 1953, 171, 964. (9) Kool, E. T. Acc. Chem. Res. 2002, 35, 936. (10) Chiba, J.; Inouye, M. Chem. Biodivers. 2010, 7, 259. (11) Krueger, A. T.; Kool, E. T. Chem Biol. 2009, 16, 242. (12) Robles, J.; Grandas, A.; Pedroso, E.; Luque, F. J.; Eritja, R.; Orozco, M. Curr. Org. Chem. 2002, 6, 1333. (13) Henry, A. A.; Romesberg, F. E. Curr. Opin. Chem. Biol. 2003, 7, 727. (14) Sivakova, S.; Rowan, S. J. Chem. Soc. Rev. 2005, 34, 9. (15) Moser, M. J.; Prudent, J. R. Nucleic Acids Res. 2003, 31, 5048.

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