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Sequence Dependent Denaturation in Small DNA Circles: A Multiscale Approach Harris, Sarah


The discovery of the structure of duplex DNA revealed how cells store genetic information. However, we are far from understanding the more complex biological question of how this information is regulated and processed by the cell. DNA topology and supercoiling is known to affect DNA transcription as changes in topology affect DNA conformation, and can thereby modify the interaction between regulatory DNA- binding proteins and their target sites and the stability of the duplex itself. At sufficiently high levels of negative supercoiling, the DNA is so destabilized that the duplex starts to denature, giving rise to a rich repertoire of structural defects whose biological importance is currently unknown. Small DNA circles offer a controllable model system for the systematic exploration of the dependence of DNA structure on supercoiling. We use computer simulation to explore the supercoiling-dependent conformation of small DNA circles and how this is affected by supercoiling, salt concentration, DNA sequence and the size of the circles [1]. The calculations use atomistic molecular dynamics simulation, and employ both implicit and explicit solvent models. However, even given the most powerful supercomputers currently available, we are unable to perform simulations over sufficiently long timescales to gain adequate statistics to quantify patterns of sequence dependent denaturation due to supercoiling. Consequently, in on going calculations we are comparing the results of the atomistic models with statistical mechanical methods [2] and coarse-grained simulations [3], which represent the DNA at the single base level. [1] Du, Q., A. Kotlyar, and A. Vologodskii, Kinking the double helix by bending deformation. Nucleic Acids Research, 2008. 36: p. 1120-1128. [2] Mitchell J. S., Laughton C. A. & Harris S. A. Atomistic simulations reveal bubbles, kinks and wrinkles in supercoiled DNA. Nucleic Acids Res. 2011. 39: p. 3928-3938. [3] Šulc P., Romano F., Ouldridge T. E, Rovigatti L., Doye J. and Louis A. A. Sequencedependent thermodynamics of a coarse-grained DNA model. J. Chem. Phys. 2012, 137, 135101. Work in collaboration with Thana Sutthibutpong, Christian Matek, Craig Benham, Gabriel Gouvea-Slade, Agnes Noy, Charlie Laughton, Elso Dringo, Jonathan Doye, Ard Loius.

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