The Transition between the B and Z Conformations of DNA Investigated by Targeted Molecular Dynamics Simulations with Explicit Solvation

Kastenholz, Mika A.; Schwartz, Thomas; Hünenberger, Philippe H.

doi:10.1529/biophysj.106.083667

Cited by 50 publications

(71 citation statements)

References 134 publications

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“…In the previous TMD simulation study on the B-Z transition, 18 it was discussed that the energetic cost caused by the loss of WC pairing is compensated for by an increase in DNA-water hydrogen bonds. A similar trend was observed in our simulation, although the change in the number of hydrogen bonds is much smaller here probably because only local changes are involved.…”

Section: Resultsmentioning

confidence: 99%

“…16 A targeted molecular dynamics simulation method (TMD) 17 was also employed to study the pathway of the B-Z transition of a hexamer, [d(GpCpGpCpGpC)] 2 , in an explicit water environment, and the potential of mean force of the transition was evaluated by integration of the driving force. 18 A common feature of the transition pathways obtained from those simulations is that the B-Z transition occurs through a stretched intermediate state in a concerted manner. Stretching and parallelization of the phosphate backbone provides enough room for base rotation and a route for backbone rewinding in the opposite direction.…”

Section: Introductionmentioning

confidence: 93%

“…In the simulated pathways backbone stretching and base-pair breaking of the entire DNA occurs simultaneously, although asynchronous base flipping was also reported. 18 The potential energy barrier of the transition, ∼100 kcal/mol, 15 and the free energy barrier, ∼30 kcal/mol, 18 are rather high, but may explain the spontaneous and reversible transition on a time scale of seconds to minutes in Z-DNA favoring environments.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Transition between B-DNA and Z-DNA: Free Energy Landscape for the B−Z Junction Propagation

Lee

Kim

et al. 2010

J. Phys. Chem. B

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Canonical, right-handed B-DNA can be transformed into noncanonical, left-handed Z-DNA in vitro at high salt concentrations or in vivo under physiological conditions. The molecular mechanism of this drastic conformational transition is still unknown despite numerous studies. Inspired by the crystal structure of a B-Z junction and the previous zipper model, we show here, with the aid of molecular dynamics simulations, that a stepwise propagation of a B-Z junction is a highly probable pathway for the B-Z transition. In this paper, the movement of a B-Z junction by a two-base-pair step in a double-strand nonamer, [d(GpCpGpCpGpCpGpCpG)] 2 , is considered. Targeted molecular dynamics simulations and umbrella sampling for this transition resulted in a transition pathway with a free energy barrier of 13 kcal/mol. This barrier is much more favorable than those obtained from previous atomistic simulations that lead to concerted transitions of the whole strands. The free energy difference between B-DNA and Z-DNA evaluated from our simulation is 0.9 kcal/mol per dinucleotide unit, which is consistent with previous experiments. The current computation thus strongly supports the proposal that the B-Z transition involves a relatively fast extension of B-DNA or Z-DNA by sequential propagation of B-Z junctions once nucleation of junctions is established.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Transition between B-DNA and Z-DNA: Free Energy Landscape for the B−Z Junction Propagation

Lee

Kim

et al. 2010

J. Phys. Chem. B

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“…From our studies we suggested that the stabilization of the Z-form is the result of a site-specific interaction by cations with the phosphate anions of the DNA backbone, vide supra. Molecular mechanics calculations, directed on the distribution of the cations over the Z-DNA surface, have also demonstrated that complexation preferentially occurs with the phosphate anions of d(C P G) and not with d(G P C) motifs of the helix [14]. With 31P nuclear magnetic resonance (NMR) measurements of the natural hexamer at different concentrations of Mg 2+ ions, an explicit selectivity between the different phosphates could be established.…”

Section: Synthesis and Characterization Of Phosphatemethylated Dnamentioning

confidence: 99%

“…Other aspects with respect to the salt-induced B-into Z-DNA transition are the corresponding conformational changes. A theoretical study has been given by Kastenholtz et al [14] using molecular dynamic simulations for a hexamer duplex with explicit solvation. Various models have been formulated for the B-into Z-dynamics.…”

Section: Synthesis and Characterization Of Phosphatemethylated Dnamentioning

confidence: 99%

A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine

Buck¹

2013

JBPC

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This study was directed on the B-into Z-DNA isomerization with alternating CG sequences monitored with artificial DNA model-systems based on methylation of the phosphate backbone. The chemical concept for this transition wherein shielding of the oxygen anions of the backbone phosphates plays an essential role, resulted in the preparation of the phosphatemethylated d(CpG). Even on this primitive level of only two base pair long, the B-Z conformational aspects of this selfcomplementary duplex could be described in solution with nuclear magnetic resonance (NMR) and circular dichroism (CD) measurements. The exclusivity of this choice became clear after synthesizing phosphatemethylated DNA with longer alternating CG fragments. It could be shown that conflicting conformational effects of the CG and GC fragments resulted in an overall B structure of the phosphatemethylated tetramer d(C P G P C P G). From our model considerations, it is clear that the internal stress introduced by the alternating CG sequences will be promoted by a complete shielding of the phosphate backbone. Elimination of this effect may be realized by a site-specific phosphate shielding. The role of the anti-syn isomerization of G in the CG fragments is clarified by methylation of the phosphate group. This anti-syn transition is absent in corresponding methylphosphonates, suggesting an exclusive role for base-backbone coordination via hydrogen bonding. In addition, we propose that the Binto Z-DNA interconversion may offer a mechanistic view for differences in dynamics between cytosine and its epigenetic derivative 5-methylcytosine. This mechanism has been extended to the demethylation of 5-methylcytosine and the exchange of information between the new epigenetic base, 5-hydroxymethylcytosine and the DNA backbone via an intramolecular phosphorylation. The role of 5-hydroxymethylcytosine in Alzheimer disease has been briefly discussed. In our opinion, this study can be considered as a new dynamic concept for epigenetics based on the dynamics of the B-Z transition in natural and phosphatemethylated DNA.

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Using the local elevation method to construct optimized umbrella sampling potentials: Calculation of the relative free energies and interconversion barriers of glucopyranose ring conformers in water

2009

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A method is proposed to combine the local elevation (LE) conformational searching and the umbrella sampling (US) conformational sampling approaches into a single local elevation umbrella sampling (LEUS) scheme for (explicit-solvent) molecular dynamics (MD) simulations. In this approach, an initial (relatively short) LE build-up (searching) phase is used to construct an optimized biasing potential within a subspace of conformationally relevant degrees of freedom, that is then used in a (comparatively longer) US sampling phase. This scheme dramatically enhances (in comparison with plain MD) the sampling power of MD simulations, taking advantage of the fact that the preoptimized biasing potential represents a reasonable approximation to the negative of the free energy surface in the considered conformational subspace. The method is applied to the calculation of the relative free energies of beta-D-glucopyranose ring conformers in water (within the GROMOS 45A4 force field). Different schemes to assign sampled conformational regions to distinct states are also compared. This approach, which bears some analogies with adaptive umbrella sampling and metadynamics (but within a very distinct implementation), is shown to be: (i) efficient (nearly all the computational effort is invested in the actual sampling phase rather than in searching and equilibration); (ii) robust (the method is only weakly sensitive to the details of the build-up protocol, even for relatively short build-up times); (iii) versatile (a LEUS biasing potential database could easily be preoptimized for small molecules and assembled on a fragment basis for larger ones).

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The Transition between the B and Z Conformations of DNA Investigated by Targeted Molecular Dynamics Simulations with Explicit Solvation

Cited by 50 publications

References 134 publications

Transition between B-DNA and Z-DNA: Free Energy Landscape for the B−Z Junction Propagation

Transition between B-DNA and Z-DNA: Free Energy Landscape for the B−Z Junction Propagation

A conformational B-Z DNA study monitored with phosphatemethylated DNA as a model for epigenetic dynamics focused on 5-(hydroxy)methylcytosine

Using the local elevation method to construct optimized umbrella sampling potentials: Calculation of the relative free energies and interconversion barriers of glucopyranose ring conformers in water

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