In this work, we used coarse-grained molecular dynamics simulations to characterize the response of circular DNA molecules to mechanical stress—specifically, how the latter influences the occurrence and the dynamical evolution of local structural defects, such as denaturation bubbles. In fact, DNA is typically depicted as a stable double helix, yet under physiological conditions it behaves as a highly dynamic molecule, seamlessly adapting its shape. The (excess) levels of mechanical stress—whether generated during transcription or imposed by cellular enzymes—play a central role in gene regulation and genome organization, and our simulations contributed to uncovering how the DNA sequence and topology shape this dynamic behavior.
The image on the cover of the December 10 issue of Biophysical Reports shows a 672-bp DNA minicircle simulated with the coarse-grained oxDNA2 model and subjected to a moderately underwound regime, where the molecule begins to release mechanical stress via the formation of so-called “plectonemic coils.” To generate this structure, we imported a simulation frame into oxView (Poppleton, E. et al. 2020. Nucleic Acids Res. 48:e72; Bohlin, J. et al. 2022. Nat. Protoc. 17:1762–1788) and colored the DNA molecule according to its local writhing. This procedure reveals key topological motifs: the apical loops, where most of the DNA writhing is concentrated, and the highly interwound supercoiled tract, where the DNA helix wraps tightly about itself. These regions are naturally highlighted by the choice of the color mapping, offering a clear visual link between the molecule’s topology and its three-dimensional configuration.
This image reflects the outcome of our work: mechanical stresses actively reshape the DNA double helix, promoting the formation of flexible, locally melted regions that might become long-lived features of the molecule, strongly biasing the global dynamics of the minicircle. In our simulations, such defects tend to form at mechanically pliable sequences (typically rich in adenine and thymine nucleobases) and mostly under higher levels of negative supercoiling. Yet, “synthetic” mismatches—mimicking the behavior of persistent denaturation bubbles—similarly steer the overall DNA architecture, suggesting a potential strategy for controlled DNA manipulation in a biotechnological context.
Although these findings arise from simulations of model DNA minicircles, the underlying principles are broadly relevant. In fact, the idea that local structural defects control the global shape of the DNA molecule might be extended to fields such as chromatin mechanics, nucleic acid engineering, and DNA-based nanotechnology. To learn more on our research interests and topics, please visit https://sbp.physics.unitn.it/.
— Manuel Micheloni, Luca Tubiana, Raffaello Potestio, and Lorenzo Petrolli