DNA double strand break (DSB) repair by non-homologous end joining (NHEJ) is initiated by DSB detection by Ku70/80 (Ku) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) recruitment, which promotes pathway progression through poorly defined mechanisms. Here, Ku and DNA-PKcs solution structures alone and in complex with DNA, defined by x-ray scattering, reveal major structural reorganizations that choreograph NHEJ initiation. The Ku80 C-terminal region forms a flexible arm that extends from the DNA-binding core to recruit and retain DNA-PKcs at DSBs. Furthermore, Ku- and DNA-promoted assembly of a DNA-PKcs dimer facilitates trans-autophosphorylation at the DSB. The resulting site-specific autophosphorylation induces a large conformational change that opens DNA-PKcs and promotes its release from DNA ends. These results show how protein and DNA interactions initiate large Ku and DNA-PKcs rearrangements to control DNA-PK biological functions as a macromolecular machine orchestrating assembly and disassembly of the initial NHEJ complex on DNA.

We employ a large scale molecular simulation based on bond-order ReaxFF to simulate the chemical reaction and study the damage to a large fragment of DNA-molecule in the solution by ionizing radiation. We illustrate that the randomly distributed clusters of diatomic OH-radicals that are primary products of megavoltage ionizing radiation in water-based systems are the main source of hydrogen-abstraction as well as formation of carbonyl-and hydroxyl-groups in the sugar-moiety that create holes in the sugar-rings. These holes grow up slowly between DNA-bases and DNA-backbone and the damage collectively propagate to DNA single and double strand break.PACS numbers: 87.64.Aa It is known that megavoltage radiation (X/γ-rays, α-particles, and heavy ions) ionizes the water molecule and creates neutral free-radicals and aqueous electrons 1-9 . In particular OH-radicals with a very short life-time that is reported to be within nano-seconds 10 , are major contributors to the single/double strand breaking of the DNA molecules and the nucleotide-base damage, as 2/3 of environment surrounding DNA molecules in the cell-nucleus is composed of water molecules 4 . Various effects of the ionizing radiation on biological systems that ranges from the development of genetic aberrations, carcinogenesis to aging, have attributed to the role of free radicals.Computational modeling is a valuable tool in understanding the basic mechanisms that underlie DNA damage. Great effort has been devoted to the statistical modeling of the damage sites based on Monte-Carlo (MC) sampling, using empirical reaction rates and radiation scattering cross-sections 4-9 . These models are limited to MC sampling on a static structure of DNA or dynamical models based on molecular-mechanics (MM) and empirical force-fields (FF), e.g. AMBER/CHARMM FF, that are developed for simulation of the non-reactive aspects of bio-molecules.The reactive aspects and the time evolution of the multi-site DNA damages driven by cascade of chemical reactions, that are beyond MM methods and empirical FF, require the calculation of the potential energies onthe-fly using first-principle quantum mechanical (QM) models. Recently ab-initio simulations of the hydrogen abstraction were developed 11-15 . However realistic modeling of DNA molecule with its environment requires extensive computer resources and is a major draw-back of QM methods. The DFT calculation for hydrogen abstraction in vacuum is limited to the initial damage of a single base [11][12][13] or single sugar-moiety 15 . Despite recent advances in QM/MM methods that allows simulation of larger molecules 14 and inclusion of solvation 15 , the real time simulation of DNA-damage remains still elusive.To address the above considerations regarding to the large scale modeling of DNA-damage, we have studied the evolution of randomly distributed hydroxyl-radicals in small pockets surrounding the DNA-molecule at room temperature using molecular dynamics simulations where the atomic interactions are described by the reactive force f...

We study magnetism in magnetically doped quantum dots as a function of confining potential, particle numbers, temperature, and strength of Coulomb interactions. We explore possibility of tailoring magnetism by controlling the electron-electron Coulomb interaction, without changing the number of particles. The interplay of strong Coulomb interactions and quantum confinement leads to enhanced inhomogeneous magnetization which persist at higher temperatures than in the noninteracting case. The temperature of the onset of magnetization can be controlled by changing the number of particles as well as by modifying the quantum confinement and the strength of Coulomb interactions. We predict a series of electronic spin transitions which arise from the competition between the many-body gap and magnetic thermal fluctuations.PACS numbers: 75.75.+a,75.50.Pp, Magnetic doping of semiconductor quantum dots (QDs) provides an interesting interplay of interaction effects in confined geometries [1,2,3,4,5,6,7,8] and potential spintronic applications [9]. In the bulk-like dilute magnetic semiconductors the carrier-mediated ferromagnetism can be photoinduced [10,11] and electrically controlled by gate electrodes [12], suggesting possible nonvolatile devices with tunable optical, electrical, and magnetic properties [9]. QDs allow for a versatile control of the number of carriers, spin, and the effects of quantum confinement which could lead to improved optical, transport, and magnetic properties as compared to their bulk counterparts [1,13,14]. Unlike in the bulk structures, adding a single carrier in a magnetic QD can have important ramifications. An extra carrier can both strongly change the total carrier spin and the temperature of the onset of magnetization which we show can be further controlled by modifying the quantum confinement and the strength of Coulomb interactions.We study the magnetic ordering of carrier spin and magnetic impurities in (II,Mn)VI QDs identified as a versatile system to demonstrate interplay of quantum confinement and magnetism [4,5,6,15,16,17,18]. Because Mn is isoelectronic with group-II elements it does not change the number of carriers which in QDs are controlled by either chemical doping or by external electrostatic potential applied to the metallic gates. The latter allows confinement of the carriers in a dot with tunable size and shape [2]. By using real space finite-temperature local spin density approximation (LSDA) [19] we study temperature (T ) evolution of magnetic properties of QDs over a large parameter space. This approach allow us to consider QDs with varying number of interacting electrons (N ) and Mn impurities (N m ) which already for small N and N m becomes computationally inaccessible to the exact diagonalization techniques [18,20]. We extend the previous studies of Coulomb interactions in magnetic QDs with N m = 1, 2 at T = 0 [18] and T > 0 results using either Thomas-Fermi approximation or by applying Hund's rule with up to 6 carriers [17]. We reveal that the interplay of strong Cou...

Understanding the damage of DNA bases from hydrogen abstraction by free OH radicals is of particular importance to understanding the indirect effect of ionizing radiation. Previous studies address the problem with truncated DNA bases as ab-initio quantum simulation required to study such electronic spin dependent processes are computationally expensive. Here, for the first time, we employ a multiscale and hybrid Quantum-Mechanical-Molecular-Mechanical simulation to study the interaction of OH radicals with guanine-deoxyribose-phosphate DNA molecular unit in the presence of water where all the water molecules and the deoxyribose-phosphate fragment are treated with the simplistic classical Molecular-Mechanical scheme. Our result illustrates that the presence of water strongly alters the hydrogen-abstraction reaction as the hydrogen bonding of OH radicals with water restricts the relative orientation of the OH-radicals with respective to the DNA base (here guanine). This results in an angular anisotropy in the chemical pathway and a lower efficiency in the hydrogen abstraction mechanisms than previously anticipated for identical system in vacuum. The method can easily be extended to single and double stranded DNA without any appreciable computational cost as these molecular units can be treated in the classical subsystem as has been demonstrated here.

We present a multi-scale simulation of the early stage of DNA damages by the indirect action of hydroxyl ((•)OH) free radicals generated by electrons and protons. The computational method comprises of interfacing the Geant4-DNA Monte Carlo with ReaxFF molecular dynamics software. A clustering method was employed to map the coordinates of (•)OH-radicals extracted from the ionization-track-structures onto nano-meter simulation voxels filled with DNA and water molecules. The molecular dynamics simulation provides the time-evolution and chemical reactions in individual simulation voxels as well as the energy-landscape accounted for the DNA-(•)OH chemical reaction that is essential for the first-principle enumeration of hydrogen abstractions, chemical bond breaks, and DNA-lesions induced by collection of ions in clusters less than the critical dimension which is approximately 2-3 Å. We show that the formation of broken bonds leads to DNA-base and backbone damages that collectively propagate to DNA single and double-strand breaks. For illustration of the methodology, we focused on particles with an initial energy of 1 MeV. Our studies reveal a qualitative difference in DNA damage induced by low energy electrons and protons. Electrons mainly generate small pockets of (•)OH-radicals, randomly dispersed in the cell volume. In contrast, protons generate larger clusters along a straight-line parallel to the direction of the particle. The ratio of the total DNA double-strand breaks induced by a single proton and electron track is determined to be ≈4 in the linear scaling limit. In summary, we have developed a multi-scale computational model based on first-principles to study the interaction of ionizing radiation with DNA molecules. The main advantage of our hybrid Monte Carlo approach using Geant4-DNA and ReaxFF is the multi-scale simulation of the cascade of both physical and chemical events which result in the formation of biological damage. The tool developed in this work can be used in the future to investigate the relative biological effectiveness of light and heavy ions that are used in radiotherapy.

Purpose We present a first‐principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra‐high‐dose‐rate (UHDR) FLASH radiotherapy. Methods We simulated damage to a segment of DNA (also representing other biomolecules such as RNA and proteins) in a simulation box filled with H2O and O2 molecules. Attoseconds physical interactions (ionizations, electronic, and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4‐DNA. Immediately after ionization, ab initio Car–Parrinello molecular dynamics (CPMD) simulation was used to identify which H2O and O2 molecules surrounding the DNA molecule were converted into reactive oxygen species (ROS). Subsequently, the femto‐ to nanosecond reactions of ROS were simulated by using MD with reactive force field (ReaxFF), to illustrate ROS merging into new types of non‐reactive oxygen species (NROS) due to strong coupling among ROS. A coarse‐grained model was constructed to describe the relevant collective phenomenon at the macroscopic level on ROS aggregation and formation of NROS agglomerates consistent with the underlying microscopic pathways obtained from MD simulations. Results Time‐dependent molecular simulations revealed the formation of metastable and transient spaghetti‐like complexes among ROS generated at UHDR. At the higher ROS densities produced under UHDR, stranded chains (i.e., NROS) are produced, mediated through attractive electric polarity forces, hydrogen bonds, and magnetic dipole–dipole interactions among hydroxyl (.OH) radicals. NROS tend to be less mobile than cellular biomolecules as opposed to the isolated and sparsely dense ROS generated at conventional dose rates (CDR). We attribute this effect to the suppression of biomolecular damage induced per particle track. At a given oxygen level, as the dose rate increases, the size and number of NROS chains increase, and correspondingly the population of toxic ROS components decreases. Similarly, at a given high dose rate, as the oxygen level increases, so do the size and number of NROS chains until an optimum level of oxygen is reached. Beyond that level, the amount of oxygen present may be sufficient to saturate the production of NROS chains, thereby reversing the sparing effects of UHDRs. Conclusions We showed that oxygen depletion, hypothesized to lead to lower normal‐tissue toxicity at FLASH dose rates, takes place within femto‐ to nanoseconds after irradiation. The mechanism is governed by the slow dynamics of chains of ROS complexes (NROS). Under physoxic (≈ 4–5% oxygen) conditions (i.e., in normal tissues), NROS are more abundant than in hypoxic conditions (e.g., <0.3% in parts of tumors), suggesting that biomolecular damage would be reduced in an environment with physoxic oxygen levels. Hence irradiation at UHDRs would be more effective for sparing physoxic normal tissues but not tumors containing regions of hypoxia. At much higher levels of oxygen (e.g., >10–1...

We study the influence of deformations on magnetic ordering in quantum dots doped with magnetic impurities. The reduction of symmetry and the associated deformation from circular to elliptical quantum confinement lead to the formation of piezomagnetic quantum dots. The strength of elliptical deformation can be controlled by the gate voltage to change the magnitude of magnetization, at a fixed number of carriers and in the absence of an applied magnetic field. We reveal a reentrant magnetic ordering with the increase of elliptical deformation and suggest that the piezomagnetic quantum dots can be used as nanoscale magnetic switches.

We introduce an approach for global fitting of the recently published high-throughput and high accuracy clonogenic cell-survival data for therapeutic scanned proton beams. Our fitting procedure accounts for the correlation between the cell-survival, the absorbed (physical) dose and the proton linear energy transfer (LET). The fitting polynomials and constraints have been constructed upon generalization of the microdosimetric kinetic model (gMKM) adapted to account for the low energy and high lineal-energy spectrum of the beam where the current radiobiological models may underestimate the reported relative biological effectiveness (RBE). The parameters (α, β) of the linear-quadratic (LQ) model calculated by the presented method reveal a smooth transition from low to high LETs which is an advantage of the current method over methods previously employed to fit the same clonogenic data. Finally, the presented approach provides insight into underlying microscopic mechanisms which, with future study, may help to elucidate radiobiological responses along the Bragg curve and resolve discrepancies between experimental data and current RBE models.