Molecular models of DNA

About: Molecular models of DNA is a research topic. Over the lifetime, 300 publications have been published within this topic receiving 16805 citations.

Molecular processes studied at a single-molecule level using DNA origami nanostructures and atomic force microscopy

Abstract: DNA origami nanostructures allow for the arrangement of different functionalities such as proteins, specific DNA structures, nanoparticles, and various chemical modifications with unprecedented precision. The arranged functional entities can be visualized by atomic force microscopy (AFM) which enables the study of molecular processes at a single-molecular level. Examples comprise the investigation of chemical reactions, electron-induced bond breaking, enzymatic binding and cleavage events, and conformational transitions in DNA. In this paper, we provide an overview of the advances achieved in the field of single-molecule investigations by applying atomic force microscopy to functionalized DNA origami substrates.

The use of branched DNA for nanoscale fabrication

Abstract: An approach to molecular nanotechnology is presented that utilizes branched DNA molecules to form stick figures. These branched molecules are directed to associate in a particular fashion by utilizing the addressability of DNA sticky ends. The sequences of molecules are designed using an algorithm that minimizes sequence symmetry. This system has been used to construct macrocycles, a DNA quadrilateral, a molecule with the connectivity of a cube and a single-stranded DNA knot. Possible uses for this system include the construction of macromolecular zeolites for structure determination by diffraction, the assembly of new catalysts, the solubilization and delivery of drugs, and the assembly of molecular electronic devices.

On the consistency of Monte Carlo track structure DNA damage simulations

Abstract: Purpose: Monte Carlo track structures (MCTS) simulations have been recognized as useful tools for radiobiological modeling. However, the authors noticed several issues regarding the consistency of reported data. Therefore, in this work, they analyze the impact of various user defined parameters on simulated direct DNA damage yields. In addition, they draw attention to discrepancies in published literature in DNA strand break (SB) yields and selected methodologies. Methods: The MCTS code Geant4-DNA was used to compare radial dose profiles in a nanometer-scale region of interest (ROI) for photon sources of varying sizes and energies. Then, electron tracks of 0.28 keV–220 keV were superimposed on a geometric DNA model composed of 2.7 × 106 nucleosomes, and SBs were simulated according to four definitions based on energy deposits or energy transfers in DNA strand targets compared to a threshold energy E TH. The SB frequencies and complexities in nucleosomes as a function of incident electron energies were obtained. SBs were classified into higher order clusters such as single and double strand breaks (SSBs and DSBs) based on inter-SB distances and on the number of affected strands. Results: Comparisons of different nonuniform dose distributions lacking charged particle equilibrium may lead to erroneous conclusions regarding the effect of energy on relative biological effectiveness. The energy transfer-based SB definitions give similar SB yields as the one based on energy deposit when E TH ≈ 10.79 eV, but deviate significantly for higher E TH values. Between 30 and 40 nucleosomes/Gy show at least one SB in the ROI. The number of nucleosomes that present a complex damage pattern of more than 2 SBs and the degree of complexity of the damage in these nucleosomes diminish as the incident electron energy increases. DNA damage classification into SSB and DSB is highly dependent on the definitions of these higher order structures and their implementations. The authors’ show that, for the four studied models, different yields are expected by up to 54% for SSBs and by up to 32% for DSBs, as a function of the incident electrons energy and of the models being compared. Conclusions: MCTS simulations allow to compare direct DNA damage types and complexities induced by ionizing radiation. However, simulation results depend to a large degree on user-defined parameters, definitions, and algorithms such as: DNA model, dose distribution, SB definition, and the DNA damage clustering algorithm. These interdependencies should be well controlled during the simulations and explicitly reported when comparing results to experiments or calculations.

Supercoiling and local denaturation of plasmids with a minimalist DNA model.

Abstract: We report molecular dynamics simulations of DNA nanocircles and submicrometer-sized plasmids with torsional stress. The multiple microseconds time scale is reached thanks to a new one-bead-per-nucleotide coarse-grained model that combines structural accuracy and predictive power, achieved by means of the accurate choice of the force field terms and their unbiased statistically based parametrization. The model is validated with experimental structural data and available all-atom simulations of DNA nanocircles. Besides reproducing the nanocircles' structures and behavior on the short time scale, our model is capable of exploring three orders of magnitude further in time and to sample more efficiently the configuration space, unraveling novel behaviors. We explored the microsecond dynamics of entire small plasmids and observed supercoiling and compaction in the overtwisted case. The stability of overtwisted nanocircles and plasmids is predicted up to macroscopic time scales. Conversely, in the undertwisted case, at physiological values of the superhelical density, after a metastable phase of supercoiling-compaction, we observe the formation and the complex dynamics of denaturation bubbles over a multiple microseconds time scale. Our results indicate that the torsional stress is involved in a delicate balance with the temperature to determine the denaturation equilibrium and regulate the transcription process.

Macroscopic modeling and simulations of supercoiled DNA with bound proteins

Abstract: General methods are presented for modeling and simulating DNA molecules with bound proteins on the macromolecular level. These new approaches are motivated by the need for accurate and affordable methods to simulate slow processes (on the millisecond time scale) in DNA/protein systems, such as the large-scale motions involved in the Hin-mediated inversion process. Our approaches, based on the wormlike chain model of long DNA molecules, introduce inhomogeneous potentials for DNA/protein complexes based on available atomic-level structures. Electrostatically, treat those DNA/protein complexes as sets of effective charges, optimized by our discrete surface charge optimization package, in which the charges are distributed on an excluded-volume surface that represents the macromolecular complex. We also introduce directional bending potentials as well as non-identical bead hydrodynamics algorithm to further mimic the inhomogeneous effects caused by protein binding. These models thus account for basic elements of protein binding effects on DNA local structure but remain computational tractable. To validate these models and methods, we reproduce various properties measured by both Monte Carlo methods and experiments. We then apply the developed models to study the Hin-mediated inversion system in long DNA. By simulating supercoiled, circular DNA with or without bound proteins, we observe significant effects of protein binding on global conformations and long-time dynamics of the DNA on the kilo basepair length.