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)] 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 free software.

Abstract:

Inverted repeat (IR) sequences in DNA can form non-canonical 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. Firstly, a twist-induced denaturation bubble must diffuse so that its midpoint is near the centre of symmetry of the IR sequence. Secondly, 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 stabilised 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 along the correlated but non-synchronous nucleation pathways we observed in direct simulations.

Abstract:

In evolution, the effects of a single deleterious mutation can sometimes be compensated for by a second mutation which recovers the original phenotype. Such epistatic interactions have implications for the structure of genome space--namely, that networks of genomes encoding the same phenotype may not be connected by single mutational moves. We use the folding of RNA sequences into secondary structures as a model genotype-phenotype map and explore the neutral spaces corresponding to networks of genotypes with the same phenotype. In most of these networks, we find that it is not possible to connect all genotypes to one another by single point mutations. Instead, a network for a phenotypic structure with n bonds typically fragments into at least 2(n) neutral components, often of similar size. While components of the same network generate the same phenotype, they show important variations in their properties, most strikingly in their evolvability and mutational robustness. This heterogeneity implies contingency in the evolutionary process.