Multiscale simulation of DNA

Dans, Pablo D.; Walther, Jürgen; Gómez, Hansel; Orozco, Modesto

doi:10.1016/j.sbi.2015.11.011

Cited by 145 publications

(137 citation statements)

References 185 publications

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“…Recent progress in force field development has corrected some of the limitations of these force fields (50–52). Based on previous evaluations (53,54), we estimate that the properties analyzed in this study are not affected by the known limitations of the force field versions we used. For ions, we used the Joung–Cheatham parameters optimized for TIP3P water (55).…”

Section: Methodsmentioning

confidence: 99%

Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome

et al. 2016

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Linker histones are essential for DNA compaction in chromatin. They bind to nucleosomes in a 1:1 ratio forming chromatosomes. Alternative configurations have been proposed in which the globular domain of the linker histone H5 (gH5) is positioned either on- or off-dyad between the nucleosomal and linker DNAs. However, the dynamic pathways of chromatosome assembly remain elusive. Here, we studied the conformational plasticity of gH5 in unbound and off-dyad nucleosome-bound forms with classical and accelerated molecular dynamics simulations. We find that the unbound gH5 converts between open and closed conformations, preferring the closed form. However, the open gH5 contributes to a more rigid chromatosome and restricts the motion of the nearby linker DNA through hydrophobic interactions with thymidines. Moreover, the closed gH5 opens and reorients in accelerated simulations of the chromatosome. Brownian dynamics simulations of chromatosome assembly, accounting for a range of amplitudes of nucleosome opening and different nucleosome DNA sequences, support the existence of both on- and off-dyad binding modes of gH5 and reveal alternative, sequence and conformation-dependent chromatosome configurations. Taken together, these findings suggest that the conformational dynamics of linker histones and nucleosomes facilitate alternative chromatosome configurations through an interplay between induced fit and conformational selection.

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Section: Methodsmentioning

confidence: 99%

Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome

et al. 2016

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“…Since the first prototypes published in the seventies, DNA force-fields have been under continuum refinement (1–6). The accessibility of an increasing amount of experimental data and the possibility to perform high-level quantum mechanical calculations has provided the required reference data for force-field refinement, but the real engine behind the improvement of force-fields has been the continuum increase in hardware and software capabilities.…”

Section: Introductionmentioning

confidence: 99%

“…In this sense, problems in twist emerging in sub-nanosecond scale parm94 (7) simulations led to the development of parm99 (8), which was the dominant force-field until multi-nanosecond trajectories reported the presence of artifactual α/γ transitions, which accumulated in time, corrupting the entire duplex (9). These issues were solved by the parmbsc0 (BSC0 from now on) revision (10), which became the ‘gold standard’ for almost a decade, until microsecond scale trajectories highlighted the existence of other errors, which required further recalibration of the force-field (1,2), leading to parmbsc1 (BSC1 from now on) (11) and to the Czech's family of force-fields (12–14) based on BSC0. A similar type of error-driven refinement happened for the CHARMM family of force-fields leading to the development of its latest two-body (15) and polarized versions (16).…”

Section: Introductionmentioning

confidence: 99%

How accurate are accurate force-fields for B-DNA?

et al. 2017

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Last generation of force-fields are raising expectations on the quality of molecular dynamics (MD) simulations of DNA, as well as to the belief that theoretical models can substitute experimental ones in several cases. However these claims are based on limited benchmarks, where MD simulations have shown the ability to reproduce already existing ‘experimental models’, which in turn, have an unclear accuracy to represent DNA conformation in solution. In this work we explore the ability of different force-fields to predict the structure of two new B-DNA dodecamers, determined herein by means of 1H nuclear magnetic resonance (NMR). The study allowed us to check directly for experimental NMR observables on duplexes previously not solved, and also to assess the reliability of ‘experimental structures’. We observed that technical details in the annealing procedures can induce non-negligible local changes in the final structures. We also found that while not all theoretical simulations are equally reliable, those obtained using last generation of AMBER force-fields (BSC1 and BSC0OL15) show predictive power in the multi-microsecond timescale and can be safely used to reproduce global structure of DNA duplexes and fine sequence-dependent details.

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“…The accuracy of MD simulations is dependent on the quality of sampling and the accuracy of the force-field [28]. Two force fields commonly used for simulations of nucleic acid-protein complexes are AMBER [29] and CHARMM [22], [23], [24], [25].…”

Section: Methodsmentioning

confidence: 99%

Molecular Mechanism of Binding between 17β-Estradiol and DNA

Hilder

Hodgkiss

2017

Computational and Structural Biotechnology Journal

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Although 17β-estradiol (E2) is a natural molecule involved in the endocrine system, its widespread use in various applications has resulted in its accumulation in the environment and its classification as an endocrine-disrupting molecule. These molecules can interfere with the hormonal system, and have been linked to various adverse effects such as the proliferation of breast cancer. It has been proposed that E2 could contribute to breast cancer by the induction of DNA damage. Mass spectrometry has demonstrated that E2 can bind to DNA but the mechanism by which E2 interacts with DNA has yet to be elucidated. Using all-atom molecular dynamics simulations, we demonstrate that E2 intercalates (inserts between two successive DNA base pairs) in DNA at the location specific to estrogen receptor binding, known as the estrogen response element (ERE), and to other random sequences of DNA. Our results suggest that excess E2 has the potential to disrupt processes in the body which rely on binding to DNA, such as the binding of the estrogen receptor to the ERE and the activity of enzymes that bind DNA, and could lead to DNA damage.

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Multiscale simulation of DNA

Cited by 145 publications

References 185 publications

Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome

Conformational selection and dynamic adaptation upon linker histone binding to the nucleosome

How accurate are accurate force-fields for B-DNA?

Molecular Mechanism of Binding between 17β-Estradiol and DNA

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