The interplay of supercoiling and thymine dimers in DNA.

Thymine dimers are a major mutagenic photoproduct induced by UV radiation. While they have been the subject of extensive theoretical and experimental investigations, questions of how DNA supercoiling affects local defect properties, or, conversely, how the presence of such defects changes global supercoiled structure, are largely unexplored. Here, we introduce a model of thymine dimers in the oxDNA forcefield, parametrized by comparison to melting experiments and structural measurements of the thymine dimer induced bend angle. We performed extensive molecular dynamics simulations of double-stranded DNA as a function of external twist and force. Compared to undamaged DNA, the presence of a thymine dimer lowers the supercoiling densities at which plectonemes and bubbles occur. For biologically relevant supercoiling densities and forces, thymine dimers can preferentially segregate to the tips of the plectonemes, where they enhance the probability of a localized tip-bubble. This mechanism increases the probability of highly bent and denatured states at the thymine dimer site, which may facilitate repair enzyme binding. Thymine dimer-induced tip-bubbles also pin plectonemes, which may help repair enzymes to locate damage. We hypothesize that the interplay of supercoiling and local defects plays an important role for a wider set of DNA damage repair systems.

Thermodynamics of star polymer solutions: A coarse-grained study.

We consider a coarse-grained (CG) model with pairwise interactions, suitable to describe low-density solutions of star-branched polymers of functionality f. Each macromolecule is represented by a CG molecule with (f + 1) interaction sites, which captures the star topology. Potentials are obtained by requiring the CG model to reproduce a set of distribution functions computed in the microscopic model in the zero-density limit. Explicit results are given for f = 6, 12, and 40. We use the CG model to compute the osmotic equation of state of the solution for concentrations c such that Φp=c∕c*≲1, where c* is the overlap concentration. We also investigate in detail the phase diagram for f = 40, identifying the boundaries of the solid intermediate phase. Finally, we investigate how the polymer size changes with c. For Φp≲0.3, polymers become harder as f increases at fixed reduced concentration c∕c*. On the other hand, for Φp≳0.3, polymers show the opposite behavior: At fixed Φp, the larger the value of f, the larger their size reduction is.

Introducing improved structural properties and salt dependence into a coarse-grained model of DNA.

We introduce an extended version of oxDNA, a coarse-grained model of deoxyribonucleic acid (DNA) designed to capture the thermodynamic, structural, and mechanical properties of single- and double-stranded DNA. By including explicit major and minor grooves and by slightly modifying the coaxial stacking and backbone-backbone interactions, we improve the ability of the model to treat large (kilobase-pair) structures, such as DNA origami, which are sensitive to these geometric features. Further, we extend the model, which was previously parameterised to just one salt concentration ([Na(+)] = 0.5M), so that it can be used for a range of salt concentrations including those corresponding to physiological conditions. Finally, we use new experimental data to parameterise the oxDNA potential so that consecutive adenine bases stack with a different strength to consecutive thymine bases, a feature which allows a more accurate treatment of systems where the flexibility of single-stranded regions is important. We illustrate the new possibilities opened up by the updated model, oxDNA2, by presenting results from simulations of the structure of large DNA objects and by using the model to investigate some salt-dependent properties of DNA.

Coarse-grained modelling of supercoiled RNA.

We study the behaviour of double-stranded RNA under twist and tension using oxRNA, a recently developed coarse-grained model of RNA. Introducing explicit salt-dependence into the model allows us to directly compare our results to data from recent single-molecule experiments. The model reproduces extension curves as a function of twist and stretching force, including the buckling transition and the behaviour of plectoneme structures. For negative supercoiling, we predict denaturation bubble formation in plectoneme end-loops, suggesting preferential plectoneme localisation in weak base sequences. OxRNA exhibits a positive twist-stretch coupling constant, in agreement with recent experimental observations.

High-functionality star-branched macromolecules: polymer size and virial coefficients.

We perform high-statistics Monte Carlo simulations of a lattice model to compute the radius of gyration Rg, the center-to-end distance, the monomer distribution, and the second and third virial coefficients of star polymers for a wide range of functionalities f, 6 ≤ f ≤ 120. We consider systems with a large number L of monomers per arm (100 is approximately < L is approximately < 1000 for f ≤ 40 and 100 is approximately < L is approximately < 400 for f = 80, 120), which allows us to determine accurately all quantities in the scaling regime. Results are extrapolated to determine the behavior of the different quantities in the limit f → ∞. Structural results are finally compared with the predictions of the Daoud-Cotton model. It turns out that the blob picture of a star polymer is essentially correct up to the corona radius Rc, which depends on f and which varies from 0.7Rg for f = 6 to 1.0Rg for f = 40. The outer region (r > Rc), in which the monomer distribution decays exponentially, shrinks as f increases, but it does not disappear in the scaling regime even in the limit f → ∞. We also consider the Daoud-Cotton scaling relation Rg (2)~f(1-ν)L(2ν), which is found to hold only for f >> 100.