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.

Conformational response of supercoiled DNA to confinement in a nanochannel.

Monte Carlo simulations were done to study the conformation of supercoiled DNA confined in a nanochannel. The molecule has a superhelical density of around -0.05 and is bathed in a monovalent salt solution with an ionic strength of 2, 10, or 150 mM. The cross-sectional diameter of the circular shaped nanochannel was varied in the range of 10 to 80 nm. The conformational properties were characterized by the writhing number and the distribution in the distance between the two opposing strands of the superhelix. With increasing confinement, as set by a smaller tube diameter and/or decreased screening of the Coulomb interaction, the supercoil becomes more tightly interwound and long-range structural features such as branching and the formation of hairpins are progressively suppressed. Analysis of the energetics shows a concurrent increase in electrostatic energy and energy of interaction of the supercoil with the wall, but the elastic twisting energy decreases. Confinement in a nanochannel or otherwise hence results in a decrease in the absolute value of the twist exerted on the duplex. The bending energy remains approximately constant, which means that there are no significant deflections from the wall. The simulation results are interpreted with theory based on the wormlike chain model, including the effects of the wall, charge, elasticity, and configurational entropy. It was found that the theory is reasonably successful in predicting the structural response to the confinement at the local level of the diameter and pitch of the supercoil.

Solitary excitations in B-Z DNA transition: a theoretical and numerical study.

The molecular mechanism of B-Z DNA transition remains elusive since the elucidation of the left-handed Z-DNA structure using atomic resolution crystallographic study. Numerous proposals for the molecular mechanism have been advanced, but none has provided a satisfactory explanation for the process. A nonlinear DNA model is proposed which enables one to derive various hypothesized molecular mechanisms, namely the Harvey model, Zang and Olson model, and the stretched intermediate model, by imposing certain constraints and conditions on the model. These constraints raise the need to reevaluate experimental investigations on B-Z DNA transition.

Molecular dynamics simulation of paracetamol molecules ordering around glycogen.

By the use of classical atomistic molecular dynamics simulations, we demonstrate that paracetamol molecules exist in a highly ordered phase in the presence of a glycogen substrate at 317 K whereas the paracetamol fluid exists in an isotropic phase in the absence of the glycogen substrate at the same temperature. This result further validates the studies made on polysaccharide regarding its abilities to promote nucleation of paracetamol via liquid preordering. As little is known regarding liquid ordering induced by a polymeric substrate, we seek to explore the ordering mechanism from an energy perspective. This is accomplished using conformation mappings. Our analysis shows that the conformation space accessible to the paracetamol molecule at 317 K in the vicinity of glycogen is smaller than the one in the absence of glycogen. An investigation on the orientation of the dipole moments of the glycogen monomers and paracetamol molecules were carried out as well. From the investigations, we show that dipolar interactions play an important role in the ordering process. These studies bear significance to the understanding of the ordering process as well as the promotion and effective control of the nucleation rate.

Applying the stochastic difference equation to DNA conformational transitions: a study of B-Z and B-A DNA transitions.

Despite the existence of numerous models to account for the B-Z DNA transition, experimenters have not yet arrived at a conclusive answer to the structural and dynamical features of the B-Z transition. By applying the stochastic difference equation to simulate the B-Z DNA transition, we have shown that the stretched intermediate model of the B-Z transition is more probable than other B-Z transition models such as the Harvey model. This is accomplished by comparing potential energy profiles of various B-Z DNA transition models and calculating relative probabilities based on the stochastic difference equation with respect to length (SDEL) formalism. The results garnered in this article allow for new approaches in determining the structural transition of B-DNA to Z-DNA experimentally. We have also simulated the B-A DNA transition using the stochastic difference equation. Unlike the B-Z DNA transition, the mechanism for the B-A DNA transition is well established. The variation in the pseudorotation angle during the transition is in good agreement with experimental results. Qualitative features of the simulated B-A transition also agree well with experimental data. The SDEL approach is thus a suitable numerical technique to compute long-time molecular dynamics trajectory for DNA molecules.

The stretched intermediate model of B-Z DNA transition.

There have been numerous attempts to describe the mechanism of B-Z transition. Our simulations based on the stochastic difference equation with length algorithm show that a short DNA oligomer will tend to unwind and overstretch during the transition. The overstretching of DNA is then understood from the Zhou, Zhang, and Ou-Yang model. Unlike the Harvey model, the stretched intermediate model does not pose any steric dilemma; we are able to show that the chain sense reversal progresses spontaneously using the stretched intermediate model. A nonlinear DNA model is used to describe the origins and mechanism of base rotation in the stretched intermediate state of DNA. We also propose an experiment that can verify the existence of a stretched intermediate state during B-Z transition, thus opening up fresh grounds for experimentation in this field.