Sequence-dependent conformational perturbation in DNA duplexes containing an
AT mismatch using molecular dynamics simulation
Anton B. Guliaev,
János Sági1 and
B. Singer2
Donner Laboratory, Life Sciences Division, Lawrence Berkeley National Laboratory University of California, Berkeley, CA 94720, USA and
1 Institute of Chemistry, Chemical Research Center, Hungarian Academy of Sciences, H-1525 Budapest, PO Box17, Hungary
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Abstract
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Previous experiments from this laboratory showed that 1,N6-ethenoadenine (
A) in 15mer DNA oligonucleotide duplexes with GG
AGG and CC
ACC central sequences is repaired 35-fold more efficiently than in duplexes containing AA
AAA and TT
ATT central sequences. This sequence dependence in repair rates appeared to correlate with the observed thermodynamic stability of these duplexes [Hang et al. (1998) J. Biol. Chem., 273, 3340633413]. In the present work, unrestrained molecular dynamics was used to evaluate the sequence-dependent structural features of these duplexes. Explicit solvent and the particle mesh Ewald method were applied for the accurate representation of the electrostatic interactions. The differences observed in the axis- and intra-base pair parameters were primarily localized at the
AT mismatch in all sequences and indicate conformational diversity between the structures. However, all four structures remained in the B-conformational family. In the tip, tilt and propeller twist parameters for the five central base pairs, larger perturbations were found for the two duplexes with
A flanked by A or T bases than for duplexes with
A flanked by G or C bases. As a result of these perturbations, the average global curvature of the AA
AAA and TT
ATT DNA duplexes was larger by ~12° than that of the duplexes with the GG
AGG and CC
ACC central sequences. The observed conformational differences between the duplexes containing A or T and G or C neighbors of
A may contribute to the observed differential enzymatic repair of the same sequences.
Abbreviations:
A, 1,N6-ethenoadenine; MD, molecular dynamics; PME, particle mesh Ewald; r.m.s.d., root mean square deviation.
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Introduction
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Sequence-dependent effects have been observed for both replication and repair of defined oligonucleotides (19). Previous studies from this laboratory focused on the sequence dependence in DNA repair and replication of exocyclic adducts (2,8,9). With 1,N6-ethenoadenine (
A) it was shown, in vitro, that the preference for the base to be inserted opposite the adduct depends on the flanking sequences (8). Another recent study demonstrated that there was also a correlation between the repair of oligonucleotide duplexes containing
A and the DNA sequence context. Repair by human or mouse alkylpurine-DNA-N-glycosylases (APNG) of duplexes with the central sequences GG
AGG or CC
ACC was 35-fold more efficient than with those containing AA
AAA or TT
ATT. The sequence-dependent differences in repair also appear to be related to the thermodynamic stability of these duplexes (9). It was therefore proposed that the stability of base pairs adjacent to the adduct can be an important factor for the efficiency of a repair enzyme, such as APNG, which requires a double-stranded DNA substrate. However, it is still unclear to what extent the sequences flanking the adduct site affect the local conformation of the duplex which may influence both recognition/enzyme binding, as well as catalytic kinetics. Structural information on defined oligonucleotide duplexes, as a function of its sequence context, should aid in clarifying the relationship between the structure and the function.
There are only a few reports on characterization of the conformation of DNA duplexes containing an
A adduct, and these do not directly address possible sequence effects (1012). The main structural feature observed with a 9mer DNA duplex of 5'-GTAC
ACATG-3' containing
A opposite T was that both
A and the T adopted anti glycosidic torsion angles and were partially stacked with the flanking base pairs. The assignment of the amino protons was consistent with the T displaced toward the 5' neighbors (10).
Recently, a number of structural studies reported sequence-dependent effects of other modified bases on DNA conformation (1320). Computational simulation using explicit solvent showed that flanking AT base pairs resulted in an enhanced flexibility of the cis, syn cyclobutanethymine dimer, but structural perturbations were small and the observed changes were not sequence dependent (20). It was further shown, using molecular modeling and NMR, that the local flexibility of the adduct studied was higher with the AT flanking base pairs than with GC pairs (18,19,21). Recent molecular modeling calculations showed strong sequence dependence for the overall curvature of the DNA containing an abasic site (14).
Molecular modeling has been utilized, not only to describe sequence-dependent effects, but also to provide insight into the local structures of duplexes containing lesions, such as thymine dimers (22), benzo[a]pyrene derivatives (2325), hydro- and hydroxy-derivatives of thymine (26) and the GT mismatch (27).
Improvements in modeling procedures and good correlations of the generated structures with NMR data suggested the use of this technique to study the conformational aspects of sequence dependent effects of the
A adduct. Accurate treatment of the long-range electrostatic forces is crucial for modeling biomolecular interactions and for simulating molecular dynamics of polyelectrolytes, such as DNA. Truncation of the long-range Coulombic forces leads to unacceptable errors affecting the stability and dynamics of the simulations (28,29), even for long cutoffs (16 Å) (30). The particle mesh Ewald (PME) method provides an excellent approximation to the full electrostatic energy while remaining computationally efficient (31,32). In particular, PME permits calculation of stable nucleic acid trajectories on the nanosecond time-scale (33,34) and reproduces sequence-specific structural effects and conformational transitions (35,36).
This paper presents the results of 500 ps simulations using explicit solvent molecules and PME treatment of the electrostatic force on the four 15mer DNA duplexes (5'-AGCGGGNNXNNGAGCT-3', where NNXNN represents: GG
AGG, CC
ACC, AA
AAA and TT
ATT), with a T opposite
A in the complementary strand (Figure 1
). The present detailed conformational analysis of these systems provides insights into the local and global structural features of the duplexes containing
A.

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Fig. 1. Sequences of the 15mer DNA oligonucleotides used in this study. For the control the A was replaced by A in all four duplexes.
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Materials and methods
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A was constructed by the addition of the exocyclic ring between N1 and N6 of the normal adenine base using the xLeap module of AMBER 5.0 (37). To obtain molecular mechanic parameters for
A, ab initio quantum mechanical methods were employed using the HyperChem 4.5 program (Hypercube, Inc., FA). The geometry was optimized with Hartree-Fock ab initio methods at the 3-21G basis set level. Atom-centered charges were obtained by fitting the electrostatic potential calculated ab initio at the 6-311G** basis set level from coordinates optimized at the 3-21G level using the routines provided by the HyperChem program. Calculated bond distances, bond angles and torsional angles were very similar to those observed crystallographically for the unmodified adenine (38). AMBER atom types were assigned according to published guidelines and torsional and bond stretching constants were scaled according to bond length (39). AMBER topology and parameter files for the four B-DNA duplexes containing 5'-AGCGGGG
AGGGAGCT-3', 5'-AGCGGCC
ACCGAGCT-3', 5'-AGCGGAA
AAAGAGCT-3' or 5'-AGCGGTT
ATTGAGCT-3' and the corresponding complementary strands were generated using the xLeap. These DNA duplexes will be referred as GG
AGG, CC
ACC, AA
AAA and TT
ATT, respectively. Additionally, four DNA duplexes of the same sequence with the
A replaced by normal A were built and used as a control for the curvature measurements. The molecular modeling procedure described below has been utilized for all eight DNA duplexes.
To neutralize negative charges on phosphates, 28 Na+ ions were placed around phosphate groups. A rectangular box was added providing at least 10 Å of explicit TIP3P water molecules around each DNA yielding approximately 4500 water molecules. The complete system of the DNA and its counterions was placed in a rectangular box of water containing approximately 14450 atoms. The exact number of atoms, water molecules and size of the water box depended on the DNA sequence.
Molecular dynamics (MD) simulations were carried out by using the SANDER module of AMBER 5.0 with SHAKE applied to all hydrogen atoms and 2 fs time steps. A 10 Å cutoff was applied to the LennardJones interactions. Constant pressure was maintained with isotropic scaling. At first, the water box was subjected to a series of equilibration MD runs while holding the solute fixed (34,40). The equilibration runs began with 1000 steps of minimization and were followed by 20 ps of MD, during which the temperature was slowly raised from 10 to 310 K over 2 ps and was maintained at 310 K for the remaining 16 ps. The size of the box was allowed to change until the water density and pressure converged to the correct values. Subsequent equilibration steps, during which position constraints on solute molecules were gradually relaxed, as well as the final production runs, were done by using the PME method to calculate electrostatic interactions (31,32). First, another 20 ps of MD were performed while still holding the solute fixed to fully relax the solvent molecules and to complete the density equilibration. This was followed by a second set of 1000 steps of minimization and 3 ps of MD, carried out with restraints on solute molecules reduced to 25 kcal/mol. Finally, five rounds of 800 steps of energy minimization were performed, during which positional restraints were reduced by 5.0 kcal/mol each round. MD production runs of 500 ps were initiated after heating the system from 10 to 310 K over 4 ps.
The MD trajectories were analyzed using the program CURVES implemented with the DIALS AND WINDOWS program (4143). The terminal base pairs were omitted in our analysis due to the known fraying effects, which were also observed in our simulations. The final structure for each duplex was produced by 1000 steps minimization of the averaged structure from the last 200 ps of MD and analyzed by the CURVES 5.3 to calculate the DNA curvature (44). Molecular structures were displayed and visually analyzed using Insight II (Insight II 98.0, Biosym/MSI, San Diego, CA). All calculations were performed on Silicon Graphics Origin 200 server interfaced with O2 work station (Silicon Graphics Inc., Mountain View, CA).
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Results and Discussion
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Root mean square deviation (r.m.s.d.)
Stability and the equilibrium state of the simulations were evaluated by calculating r.m.s.d. values of each 1 ps `snapshot' relative to the coordinates of the initial (energy-minimized) structures for all four lesion-containing duplexes. A plot of the r.m.s.d. values as a function of the simulation time is shown in Figure 2
. The duplex structures containing TT
ATT and CC
ACC central sequences reached the conformational equilibrium and r.m.s.d. values showed plateau after 150 ps. The equilibrium for the AA
AAA and GG
AGG structures was observed after 200 and 300 ps, respectively. Therefore, only conformations generated during the 300500 ps period of simulations were used to monitor the structure properties. For the AA
AAA structure a slightly higher average r.m.s.d. was measured (3.23 ± 0.7 Å) than for the GG
AGG (2.31 ± 0.5 Å), CC
ACC (2.72 ± 0.5Å) or TT
ATT structures (2.77 ± 0.5 Å).
Hydrogen bonding
An important indicator for the stability of duplex structures is the length of hydrogen bonds and percentage occupancy during the MD simulations. All hydrogen bonds were evaluated during the last 200 ps of the MD. The plots of WatsonCrick hydrogen bond values for the four central base pairs of the four duplexes are shown in Figure 3
. No hydrogen bonding was observed in the
AT mismatch. There was no other disruption of the hydrogen bonds in any of the four structures and the majority were 100% occupied during the simulation. However, a slight weakening was observed at one of the hydrogen bonds at the AT base pair flanking the adduct site in both the AA
AAA and TT
ATT structures. The A7N6T24O4 bond in the case of the AA
AAA duplex (Figure 3A
) and the T9O4A22N6 bond for the TT
ATT duplex (Figure 3B
) show larger average values and also larger fluctuations around their average values than the rest of the hydrogen bonds. The average value for the A7N6T24O4 was 3.24 ± 0.4 Å and for the T9O4A22N6 the average was 3.15 ± 0.34 Å, with the 90 and 93% occupancy, respectively. The rest of the hydrogen bonds for all four duplexes falls into the range of the 2.98 ± 0.16 Å, which is the standard range in the WatsonCrick alignment (45).
The higher values for the two hydrogen bonds can be associated with the decrease of bond angle due to significant buckling and propeller twist of the A7T24 base pair in AA
AAA and the T9A22 pair in TT
ATT structures. The hydrogen bond angles, defined by three atoms, N6, H61 and O4, were 20 ± 10 and 17 ± 8°, respectively. The rest of the hydrogen bond angles fell into the range of 11 ± 7°. Distortion of base pairs due to the presence of a lesion has been reported for other adducts. A 0.5 Å increase in bond length has been observed for the cis, syn cyclobutanethymine dimer (22). The imino proton spectra obtained by NMR supported this observation (46).
Conformational analysis
Global helicoidal parameters
The overall conformation of the four
A-containing duplexes was found to remain in the B-conformation during the entire course of the simulations. There are, however, numerous conformational differences between the four structures.
The average values from the last 200 ps of MD of the inter-, intra- and axis-base pair parameters for the four DNA duplexes, as well as the schematic definition of these parameters can be found in Figures 46

. Values for the helicoidal parameters for the AA
AAA structure are plotted together with GG
AGG and the values for TT
ATT are together with CC
ACC on the separate columns in Figures 46

.
Conformation of the
A8T23 mismatch
Conformation of the mismatch can be described by the axis- and intra-base pair parameters (Figures 4 and 5
). Only a subset of these parameters deviates strongly from the values expected for B-DNA. XDP, which shows the displacement of base pairs along the x-axis, indicates the displacement of the mismatch toward the major groove (positive sign) in all four modified duplexes (Figure 4
). The rest of the base pairs show XDP values characteristics of the B-DNA (0 and 0.7 Å).
The displacement along the y-axis (YDP) for the
A8T23 mismatch also shows significant deviation from the B-DNA values (0 Å), except for the GG
AGG duplex which shows an average YDP of 0.03 Å (Figure 4
).
Four out of the six intra-base pair parameters also showed differences in mismatch conformation (Figure 5
). The linear in-plane displacement of one base with respect to the other along the x-axis can be described by the shear (SHR) parameter. SHR showed difference between the duplexes and it's value deviated significantly from those for the standard B-DNA. All four structures showed significant increases in the stretch (STR) parameter, which is an indicator of linear in-pair displacement along the y-axis. The highest value was observed for the AA
AAA duplex (1.28 Å), while the lowest was observed for the GG
AGG structure (0.45Å). The rest of the base pairs in all four DNA duplexes have the values close to 0 (Figure 5
), which is typical for both A and B forms of DNA. The out-of-plane linear displacement is shown by the stagger (STG) parameter. STG showed the separation of the bases along the z-axis in all four structures. The largest deviation from the B-DNA value was found for the CC
ACC duplex (1.32 Å) (Figure 5
). The OPN parameter, which also describes the geometry of base pairing (Figure 5
), showed large positive values for the mismatch and indicated the opening toward the major groove. The large opening for
A8T23 is characteristic of the lesion site itself and is independent of the sequence context.
Effect of the flanking sequences on
A8T23 conformation
Conformation of the mismatch proved to be significantly different from the rest of the base pairs of the 15mer duplexes studied and varied with the flanking sequences. Pronounced differences were observed in a number of the axis- and inter-base pair parameters: XDP, YDP, SHR, STR and STG (Figures 4 and 5
).
XDP was different for the duplexes with purine or pyrimidine flanking bases (Figure 4
). For better characterization, the separate displacements of the bases within the mismatch were also calculated. The largest displacement of
A toward the major groove was observed in the AA
AAA structure (1.42 Å), while the opposite T remained stacked directly underneath the T22. In the GG
AGG structure the opposite movement was observed: the
A remained stacked in the duplex, while the opposite T (T23) swung into the major groove. The displacement for this base was 1.53 Å. In the TT
ATT and CC
ACC duplexes the
A remained stuck into the duplex while the opposite T was displaced toward the major grove to different extents: 0.6 and 1.60 Å for the TT
ATT and CC
ACC, respectively.
A positive SHR value was observed for the mismatch in the AA
AAA duplex (4.26 Å) which indicates a significant displacement of the
A toward the major groove (Figure 5
). In contrast, a negative value was found for the GG
AGG duplex (3.54 Å), which may indicate that T23 is shifted toward the major groove, but not
A. A difference in the magnitude of the SHR was observed between the TT
ATT and CC
ACC sequences, indicating various extents of displacement of T23 into the major groove. However, the opposite direction of the STG was observed between the CC
ACC and TT
ATT structures, which points to different alignments of the bases in the mismatch. The opposite direction in STG was also observed between AA
AAA and GG
AGG duplexes (Figure 5
).
Effect of the
A8T23 mismatch on the conformation of flanking sequences
Several parameters showed significant differences in values for the duplexes with different flanking bases, which may indicate the effect of the mismatch on the conformation of the neighboring bases. The tip (TIP) parameter, which shows the inclination along the y-axis showed large deviations from B-DNA values (05°) for at least five central base pairs, including the mismatch, for all four structures (Figure 3
). The largest value of 14° was observed for the
AT mismatch in the TT
ATT structure. All four duplexes exhibited various buckling (BKL) at the central five base pairs, comparable with the rest of the DNA (Figure 5
). Considerable propeller twist (PRP) was observed for the mismatch and flanking base pairs (between 15 and 30°) (Figure 5
). The average PRP value for the rest of the base pairs was at 10°.
The distortions observed in geometry of the base pairs adjacent to the mismatch site correlate with the weakening of the hydrogen bonding at the AA
AAA and TT
ATT structures. Both A7T24 (AA
AAA) and T9A22 (TT
ATT) exhibited large values for the BKL (17 and 32°, respectively) and PRP (18 and 25°, respectively) (Figure 5
).
Perturbations in inter-base pair parameters, which probably best describe the stacking interactions, were also detected. These were observed for the tilt (TLT), roll (ROL) and twist (TWS) parameters (Figure 6
). Both the
A8T23/A7T24 and the
A8T23/T7A24 base pair steps in AA
AAA and TT
ATT structures, respectively, exhibited significantly larger TLT values than did the
A8T23/G7C24 and
A8T23/C7G24 base pair steps in GG
AGG and CC
ACC. Moreover, the presence of the mismatch in the TT
ATT structure showed significant changes in the TLT parameter up 2 bp steps away from the central
A8T23/T7A24 step (T10A21/T9A22). In the AA
AAA duplex, larger values were observed for the TLT in the
A8T23/A7T24 and A9T22/
A8T23 steps than in the corresponding
A8T23/G7C24 and G9C22/
A8T23 steps in GG
AGG structure. A significant difference was observed in the TWS value between the GG
AGG and AA
AAA structures (Figure 6
). The large value of the TWS for the
A8T23/A7T24 step (48°) indicates a large helical twist in the AA
AAA structure at this base pair step. In contrast, the
A8T23/G7C24 step in GG
AGG showed only a small TWS value (13°). This small TWS value is an indicator of untwisting of the DNA helix at the lesion site. In contrast, the RIS parameter, which indicates vertical displacement of one base pair with respect to an other, remained in the range for the canonical B-DNA (average value 3.38 Å) for all base pair steps, including the mismatch.
Backbone conformation
The presence of the
A8T23 mismatch does not appear to have a significant impact on backbone conformation of the duplexes studied (data not shown). Small deviations were observed at the mismatch site and these resulted in visible kinks in the backbone. The rest of the sugar-phosphate backbone remained in the range expected for the B-DNA family. The N-glycosidic torsion angles were in the anti or high anti conformation for all bases, including the adduct. Minor distortions were observed for the sugar puckering for the
A8 and the opposite T23. The average values for sugar puckering during the last 200 ps of the simulations are summarized in Table I
.
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Table I. Average values for the sugar conformation for the four 15mer DNA duplexes during the last 200 ps of the molecular dynamics simulations
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DNA bending
To assess a global effect of the altered helical parameters on DNA structure, the bending or curvature of the
A-containing, as well as the unmodified, duplexes was calculated using the CURVES5.3 algorithm. The results showed that both the unmodified and the adduct-containing duplexes were bent to different extents. The magnitude of bending was, however, greater with
A than with A (Table II
). The average curvature of the unmodified double helices was 11.4°. Duplexes with central AAAAA or TTATT sequences were more bent than were the duplexes with central GGAGG or CCACC sequences. High curvature values ranging from 10 to 22° for various adeninethymine tracts have been reported (44).
The present calculations indicated that the bending values of the
A-containing duplexes were larger than those of the corresponding controls. The extent of bending differed with the sequences flanking the adduct (Figure 7
). In the case of the AA
AAA structure, the average value for the overall curvature over the last 200 ps of MD simulation was 27.6°. A very similar value, 26.8°, was observed for the TT
ATT duplex. Significantly smaller curvature was found for the GG
AGG and CC
ACC structures, 11.7 and 17.8°, respectively (Table II
). Bending occurs toward the major groove and at the mismatch site, with the exception of the AA
AAA duplex where bending occurs at the 5' base pair step prior to the mismatch. Overall, for the duplexes with A or T flanking base pairs, the average curvature (27.2 ± 0.4°) was larger by 12.4° than for the duplexes with the C or G flanking sequences (14.8 ± 3°). The average increase in DNA bending of
A-containing duplexes with G or C flanking doublets was 6.3°, while duplexes with A or T flanking have an average increase of 12.9° (Table II
, column
). According to these data, the
A adduct increased DNA bending almost 2-fold and the magnitude of increase was sequence dependent. The higher degree of bending for the AT-containing duplexes more likely correlates with the abrupt changes in TLT, TIP, ROL and PRP parameters of the central sequences of these structures.
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Summary
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It has been shown that repair of DNA lesions can be influenced by sequence context. One of these lesions is the
A adduct, and the sequence-dependent repair by human APNG of this adduct has been studied previously in this laboratory (9). In the present study, the
AT mismatch-induced structural distortions of 15mer DNA duplexes were analyzed by molecular modeling, as a function of the sequences flanking the adduct. For this purpose, flanking AA, TT, GG or CC neighbor nucleotides were used at the central mismatch site in four different duplexes.
The global feature of the four
A-containing double-stranded structures is that, generally, the torsion angles of the phosphodiester backbone remained in the domain of the B-DNA family. However, a number of helical parameters deviated significantly from those characterizing B-DNA, and the deviations varied with the context of the bases flanking
A. The main conformational changes were observed locally at the adduct site and were mainly restricted to the two neighboring base pair steps.
The conformation of the
AT mismatch differs markedly from the the conformation of WatsonCrick base pairs.
A and the opposite T are both horizontally and vertically displaced, which results in an opening of the pair, and no hydrogen bonds were observed. The mismatch is displaced toward the major groove in all four structures.
The sequences flanking the mismatch had significant effects on conformational perturbation of the central sequences for the duplexes. The inter-base pair parameters, which describe the geometry of base stacking, indicate that the AA
AAA and TT
ATT structures have larger perturbations in stacking interactions than in the GG
AGG and CC
ACC structures. These perturbations were mainly in the tilting angles, up to 2 bp away from the
AT site. These differences can be attributed to the known flexibility of the AT base pair, which might be enhanced by the presence of the mismatch.
Hydrogen bonds were not disrupted in the flanking base pairs and most of these bonds were 100% occupied during the entire simulation. However, a slight weakening of one of the hydrogen bonds at the flanking AT and TA base pairs was observed and occupancy values were 90 and 93%, respectively, for the AA
AAA and TT
ATT duplex structures.
All four
A-containing duplexes were bent at or around the mismatch site. The AA
AAA and TT
ATT duplexes were bent to a similar extent (27.6 and 26.8°), whereas bending was smaller for the GG
AGG (11.7°) and CC
ACC (17.8°) structures. The duplexes with A or T neighbor bases were more bent, by an average of 12.4°, than the duplexes with flanking G or C bases. The increase in bending for the structures with a flanking A or T may correlate with the larger distortions observed in the axis- and inter-base pair parameters mentioned above. However, the bending might be also a result of a large number of the small conformational changes, rather than a few main ones. These results indicate that the effect of the
AT mismatch on the global DNA curvature depends on the sequence context.
The present work provides some structural insights into the possible conformations of the
AT mismatch-containing duplexes, which may be relevant to the interaction of the APNG enzyme to the modified DNA. It is known that the enzyme is able to recognize a variety of structural perturbations of the modified DNA at/or around the lesion site (47). Based on our calculations, structural perturbations in
A-containing 15mer DNA duplexes were shown to be affected by the sequence context of the flanking bases. The major structural perturbation observed in this work was the significant increase of bending of the duplexes with A or T sequences flanking the adduct site. These duplexes were earlier found to be thermodynamically less stable (9). Based on the present work it may be reasonable to assume that the larger perturbations, especially the higher curvature, observed with A- or T-neighbor-containing duplexes may contribute to the reduced repair efficiency of
A by APNG.
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Notes
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2 To whom correspondence should be addressed. Email: abguliaev{at}lbl.gov 
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Acknowledgments
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This work was supported by NIH grants CA 47723 and CA 72079 (to B.S.) and was administered by the Lawrence Berkeley National Laboratory under Department of Energy contract DE-AC03-76SF00098.
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Received March 14, 2000;
revised May 18, 2000;
accepted May 24, 2000.