Ard Louis

Abstract:

We introduce a sequence-dependent parametrization for a coarse-grained DNA model [T. E. Ouldridge, A. A. Louis, and J. P. K. Doye, J. Chem. Phys. 134, 085101 (2011)]10.1063/1.3552946 originally designed to reproduce the properties of DNA molecules with average sequences. The new parametrization introduces sequence-dependent stacking and base-pairing interaction strengths chosen to reproduce the melting temperatures of short duplexes. By developing a histogram reweighting technique, we are able to fit our parameters to the melting temperatures of thousands of sequences. To demonstrate the flexibility of the model, we study the effects of sequence on: (a) the heterogeneous stacking transition of single strands, (b) the tendency of a duplex to fray at its melting point, (c) the effects of stacking strength in the loop on the melting temperature of hairpins, (d) the force-extension properties of single strands, and (e) the structure of a kissing-loop complex. Where possible, we compare our results with experimental data and find a good agreement. A simulation code called oxDNA, implementing our model, is available as a free software. © 2012 American Institute of Physics.

Abstract:

Inverted repeat (IR) sequences in DNA can form noncanonical cruciform structures to relieve torsional stress. We use Monte Carlo simulations of a recently developed coarse-grained model of DNA to demonstrate that the nucleation of a cruciform can proceed through a cooperative mechanism. First, a twist-induced denaturation bubble must diffuse so that its midpoint is near the center of symmetry of the IR sequence. Second, bubble fluctuations must be large enough to allow one of the arms to form a small number of hairpin bonds. Once the first arm is partially formed, the second arm can rapidly grow to a similar size. Because bubbles can twist back on themselves, they need considerably fewer bases to resolve torsional stress than the final cruciform state does. The initially stabilized cruciform therefore continues to grow, which typically proceeds synchronously, reminiscent of the S-type mechanism of cruciform formation. By using umbrella sampling techniques, we calculate, for different temperatures and superhelical densities, the free energy as a function of the number of bonds in each cruciform arm along the correlated but asynchronous nucleation pathways we observed in direct simulations. © 2012 American Chemical Society.