Structural and dynamic effects of single 7-hydro-8-oxoguanine bases located in a frameshift target DNA sequence

Barone, Flavia; Lankaš, Filip; Špačková, Nad'a; Šponer, Jiřı́; Karran, Peter; Bignami, Margherita; Mazzei, Filomena

doi:10.1016/j.bpc.2005.06.003

Cited by 22 publications

(31 citation statements)

References 36 publications

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“…It is also known that not all aspects of the sequence-dependent local conformational variability of double helices are perfectly reproduced, and the structures simulated with AMBER force fields even appear to be subtly shifted from the typical B-DNA structure toward the A-DNA form. 71 Recently, a particularly serious problem (an accumulation of incorrect R/γ backbone substate occurring [72][73][74] in longer B-DNA simulations with parm99 (or older) 75 AMBER force field versions) was identified, and usable force field correction (called parmbsc0) of this behavior was introduced. 76 However, despite all the limitations, the simulations at least partly reflect the effect of stacking on the fine double-helix structure, allow for monitoring eventual conformational substates, and neatly eliminate any pathological steric clashes.…”

Section: Methodsmentioning

confidence: 99%

“…78 All simulations were carried out using the AMBER 8 suite of programs 78 and the parm99 force field. 75 The trajectories were monitored for the presence of the R/γ noncanonical (γ-trans) backbone flips, [72][73][74] and all base pair step geometries with such γ-trans flips were discarded. Note that during preparation of this study, the corrected parmbsc0 version of the force field, effectively suppressing the R/γ flips, has been released.…”

Section: Methodsmentioning

confidence: 99%

“…One of the purposes of this study was to monitor changes of base stacking energies along the trajectories. For the DNA simulations, one step for each unique dinucleotide sequence where no R/γ backbone flip [72][73][74] occurred within the whole 20 ns trajectory was identified. For these steps, fifty structures averaged over 400 ps were generated for each of 20 ns trajectory using the ptraj module of Amber 8.…”

Section: Methodsmentioning

confidence: 99%

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Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Svozil¹,

Hobza²,

Šponer³

2010

J. Phys. Chem. B

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High level ab initio methods have been used to study stacking interactions in ten unique base pair steps both in A-RNA and in B-DNA duplexes. The protocol for selection of geometries based on molecular dynamics (MD) simulations is proposed, and its suitability is demonstrated by comparison with stacking in steps at fiber diffraction geometries. It is shown that fiber diffraction geometries are not sufficiently accurate for interaction energy calculations. In addition, the protocol for selection of geometries based on MD simulations allows for the evaluation of the variability of the intrinsic stacking energies along the MD trajectories. The uncertainty in stacking energies (difference between the most and least stable geometry) due to the dynamical nature of systems can be, in some cases, as large as 3.0 kcal · mol, which is almost 50% of the actual sequence dependence of base stacking energies (the energy difference between the most and least stable sequences). Thus, assessing the relative magnitude of the gas phase stacking energy using a single geometry for each sequence is insufficient to obtain an unambiguous order of gas phase stacking energies in canonical double helices. Though the ordering of ten unique dinucleotide steps cannot be definitive, some general conclusions were drawn. The stacking energies of base pair steps in A-RNA are more evenly separated compared to B-DNA, and their ordering is less sensitive to the dynamics of the system compared to be B-DNA. The most stable step both in B-DNA and A-RNA is the CG/CG step that is well separated from the second most stable step GC/GC. Also the least stable step (the CC/GG step) is well separated from the rest of the structures. The calculations further show that B-DNA stacking is favorable only marginally (on average by 1.14 kcal · mol -1 per base pair step) over A-RNA stacking, and this difference vanishes after subtracting the stabilizing van der Waals effect of the thymine 5-methyl group that is absent in RNA. Basically, no correlation between the sequence dependence of gas phase stacking energies and the sequence dependence of ∆G°3 7 free energies used in nearest-neighbor models was found either for B-DNA or for A-RNA. This reflects the complexity of the balance of forces that are responsible for the sequence dependence of thermodynamics stability of nucleic acids, which masks the effect of the intrinsic interactions between the stacked base pairs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Svozil¹,

Hobza²,

Šponer³

2010

J. Phys. Chem. B

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“…Recent AMBER MD studies of B-DNA duplexes [56][57][58] reported long-lived -''switched'' conformations in DNA sugar-phosphate backbone. These alternative conformations appeared irreversible, and caused a reduction of helical twist and some other structural effects.…”

Section: Phosphate Backbone and Helical Parameters Indicate A Good Pementioning

confidence: 99%

Structure, dynamics, and elasticity of free 16s rRNA helix 44 studied by molecular dynamics simulations

et al. 2006

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Molecular dynamics (MD) simulations were employed to investigate the structure, dynamics, and local base-pair step deformability of the free 16S ribosomal helix 44 from Thermus thermophilus and of a canonical A-RNA double helix. While helix 44 is bent in the crystal structure of the small ribosomal subunit, the simulated helix 44 is intrinsically straight. It shows, however, substantial instantaneous bends that are isotropic. The spontaneous motions seen in simulations achieve large degrees of bending seen in the X-ray structure and would be entirely sufficient to allow the dynamics of the upper part of helix 44 evidenced by cryo-electron microscopic studies. Analysis of local base-pair step deformability reveals a patch of flexible steps in the upper part of helix 44 and in the area proximal to the bulge bases, suggesting that the upper part of helix 44 has enhanced flexibility. The simulations identify two conformational substates of the second bulge area (bottom part of the helix) with distinct base pairing. In agreement with nuclear magnetic resonance (NMR) and X-ray studies, a flipped out conformational substate of conserved 1492A is seen in the first bulge area. Molecular dynamics (MD) simulations reveal a number of reversible alpha-gamma backbone flips that correspond to transitions between two known A-RNA backbone families. The flipped substates do not cumulate along the trajectory and lead to a modest transient reduction of helical twist with no significant influence on the overall geometry of the duplexes. Despite their considerable flexibility, the simulated structures are very stable with no indication of substantial force field inaccuracies.

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“…The g + /t and g -/t conformations are the problematic substates that tend to accumulate in longer B-DNA simulations with Amber force fields. 21, 64,65 As explained in the Methods section, because of the complexity of the PES, the lowest-lying minima cannot be guaranteed to be found for all the investigated R/γ regions. The structures were generally obtained by starting from the canonical geometry, subsequently setting up the target R/γ combination while keeping other angles constant (at their canonical values) and finally optimizing the structures with fixed R and γ.…”

Section: Figurementioning

confidence: 99%

Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

Svozil¹,

Šponer²,

Marchán³

et al. 2008

J. Phys. Chem. B

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The anionic sugar-phosphate backbone of nucleic acids substantially contributes to their structural flexibility. To model nucleic acid structure and dynamics correctly, the potentially sampled substates of the sugar-phosphate backbone must be properly described. However, because of the complexity of the electronic distribution in the nucleic acid backbone, its representation by classical force fields is very challenging. In this work, the three-dimensional potential energy surfaces with two independent variables corresponding to rotations around the R and γ backbone torsions are studied by means of high-level ab initio methods (B3LYP/ 6-31+G*, MP2/6-31+G*, and MP2 complete basis set limit levels). [3817][3818][3819][3820][3821][3822][3823][3824][3825][3826][3827][3828][3829] force fields to describe the various R/γ conformations of the DNA backbone accurately is assessed by comparing the results with those of ab initio quantum chemical calculations. Two model systems differing in structural complexity were used to describe the R/γ energetics. The simpler one, SPM, consisting of a sugar and methyl group linked through a phosphodiester bond was used to determine higher-order correlation effects covered by the CCSD(T) method. The second, more complex model system, SPSOM, includes two deoxyribose residues (without the bases) connected via a phosphodiester bond. It has been shown by means of a natural bond orbital analysis that the SPSOM model provides a more realistic representation of the hyperconjugation network along the C5′-O5′-P-O3′-C3′ linkage. However, we have also shown that quantum mechanical investigations of this model system are nontrivial because of the complexity of the SPSOM conformational space. A comparison of the ab initio data with the ff99 potential energy surface clearly reveals an incorrect ff99 force-field description in the regions where the γ torsion is in the trans conformation. An explanation is proposed for why the R/γ flips are eliminated so successfully when the parmbsc0 force-field modification is used.

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Structural and dynamic effects of single 7-hydro-8-oxoguanine bases located in a frameshift target DNA sequence

Cited by 22 publications

References 36 publications

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Comparison of Intrinsic Stacking Energies of Ten Unique Dinucleotide Steps in A-RNA and B-DNA Duplexes. Can We Determine Correct Order of Stability by Quantum-Chemical Calculations?

Structure, dynamics, and elasticity of free 16s rRNA helix 44 studied by molecular dynamics simulations

Geometrical and Electronic Structure Variability of the Sugar−phosphate Backbone in Nucleic Acids

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