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Dynamical control of denaturation bubble nucleation in supercoiled DNA minicircles

François Sicard, Nicolas Destainville, Philippe Rousseau, Catherine Tardin, and Manoel Manghi
Phys. Rev. E 101, 012403 – Published 8 January 2020
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  • INTRODUCTION
  • NUMERICAL MODEL
  • RESULTS AND DISCUSSION
  • CONCLUSION
  • ACKNOWLEDGMENTS
  • APPENDICES
    • References

    Abstract

    We examine the behavior of supercoiled DNA minicircles containing between 200 and 400 base-pairs, also named microDNA, in which supercoiling favors thermally assisted DNA denaturation bubbles of nanometer size and controls their lifetime. Mesoscopic modeling and accelerated dynamics simulations allow us to overcome the limitations of atomistic simulations encountered in such systems, and offer detailed insight into the thermodynamic and dynamical properties associated with the nucleation and closure mechanisms of long-lived thermally assisted denaturation bubbles which do not stem from bending- or torque-driven stress. Suitable tuning of the degree of supercoiling and size of specifically designed microDNA is observed to lead to the control of opening characteristic times in the millisecond range, and closure characteristic times ranging over well distinct timescales, from microseconds to several minutes. We discuss how our results can be seen as a dynamical bandwidth which might enhance selectivity for specific DNA binding proteins.

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    • Received 4 August 2019

    DOI:https://doi.org/10.1103/PhysRevE.101.012403

    ©2020 American Physical Society

    Physics Subject Headings (PhySH)

    1. Research Areas
    Kinetic theoryThermodynamics
    1. Physical Systems
    DNA
    Polymers & Soft Matter

    Authors & Affiliations

    François Sicard1,*, Nicolas Destainville2, Philippe Rousseau3, Catherine Tardin4, and Manoel Manghi2

    • 1Department of Chemistry, King's College London, SE1 1DB London, United Kingdom
    • 2Laboratoire de Physique Théorique, IRSAMC, Université de Toulouse, CNRS, UPS, France
    • 3Laboratoire de Microbiologie et Génetique Moléculaires, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, France
    • 4Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, CNRS, UPS, France

    • *Corresponding author: francois.sicard@free.fr

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    Issue

    Vol. 101, Iss. 1 — January 2020

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    • Figure 1
      Figure 1

      Snapshot of an equilibrated double helix (from Ref. [26]). The bending angle along each strand is θref, ρref is the equilibrium base-pair distance, and n̂ is the helical axis around which twist is defined. The imposed equilibrium twist between successive pairs is ϕref.

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    • Figure 2
      Figure 2

      Equilibrium snapshots of (a) circular DNA with pitch p=12.0 base-pairs (cDNA0) and (b) linear dsDNA (ℓDNA) when the long-lived denaturation bubble is formed. The AT-rich region of size 30 base-pairs (red) is delimited at each extremity by two sequences of 10 GC bps aligned arbitrarily along the Z-axis (blue). cDNA0 is closed by a circular GC region (grey). The maximal distance between paired bases, ρmax, and the minimal twist angle between successive bps, ϕmin, defined in the main text are shown. (c) Free energy profiles associated with the opening and closure mechanism of ℓDNA and cDNA0 projected along ρmax. The location of the transition state, ρ★, is shown.

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    • Figure 3
      Figure 3

      Free energy surface of ℓDNA (a), cDNA0 (b), cDNA2a (c), and cDNA3a (d) projected along the maximal distance between paired bases, ρmax, and the minimal twist angle between successive bps, ϕmin, defined in the main text in the linear and circular DNAs reported in Table 1. The free energy basins associated with the open (op) and closed (cl) states of the DNA bubble, the location of the transition state (ρ★), and the typical minimal free energy paths obtained within the steepest descent framework (red) are shown.

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