A molecular dynamics simulation of DNA damage induction by ionizing radiation.

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.

Spin textures in strongly coupled electron spin and magnetic or nuclear spin systems in quantum dots.

Controlling electron spins strongly coupled to magnetic and nuclear spins in solid state systems is an important challenge in the field of spintronics and quantum computation. We show here that electron droplets with no net spin in semiconductor quantum dots strongly coupled with magnetic ion or nuclear spin systems break down at low temperature and form a nontrivial antiferromagnetic spatially ordered spin texture of magnetopolarons. The spatially ordered combined electron-magnetic ion spin texture, associated with spontaneous symmetry breaking in the parity of electronic charge and spin densities and magnetization of magnetic ions, emerges from an ab initio density functional approach to the electronic system coupled with mean-field approximation for the magnetic or nuclear spin system. The predicted phase diagram determines the critical temperature as a function of coupling strength and identifies possible phases of the strongly coupled spin system. The prediction may arrest fluctuations in the spin system and open the way to control, manipulate, and prepare magnetic and nuclear spin ensembles in semiconductor nanostructures.

Multiscale QM/MM molecular dynamics study on the first steps of guanine damage by free hydroxyl radicals in solution.

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 simulations 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 a guanine-deoxyribose-phosphate DNA molecular unit in the presence of water, where all of 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 respect 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 systems 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.

Computational studies for reduced graphene oxide in hydrogen-rich environment.

We employ molecular dynamic simulations to study the reduction process of graphene oxide (GO) in a chemically active environment enriched with hydrogen. We examine the concentration and pressure of hydrogen gas as a function of temperature in which abstraction of oxygen is possible with minimum damage to C-sp(2) bonds, hence preserving the integrity of the graphene sheet. Through these studies we find chemical pathways that demonstrate beneficiary mechanisms for the quality of graphene including formation of water as well as suppression of carbonyl pair holes in favor of hydroxyl and epoxide formation facilitated by hydrogen gas in the environment.

Reactive molecular dynamics study on the first steps of DNA damage by free hydroxyl radicals.

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 propagates to a DNA single and double strand break.

DNA-backbone radio resistivity induced by spin blockade effect.

Coherent control of OH-free radicals interacting with the spin-triplet state of a DNA molecule is investigated. A model Hamiltonian for molecular spin singlet-triplet resonance is developed. We illustrate that the spin-triplet state in DNA molecules can be efficiently populated, as the spin-injection rate can be tuned to be orders of magnitudes greater than the decay rate due to small spin-orbit coupling in organic molecules. Owing to the nano-second life-time of OH free radicals, a non-equilibrium free energy barrier induced by the injected spin triplet state that lasts approximately longer than one-micro second in room temperature can efficiently block the initial Hydrogen abstraction and DNA damage. For a direct demonstration of the spin-blockade effect, a molecular simulation based on an ab-initio Car-Parrinello molecular dynamics is deployed.

Ku and DNA-dependent protein kinase dynamic conformations and assembly regulate DNA binding and the initial non-homologous end joining complex.

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.

General strategy for the protection of organs at risk in IMRT therapy of a moving body.

We investigated protection strategies of organs at risk (OARs) in intensity modulated radiation therapy (IMRT). These strategies apply to delivery of IMRT to moving body anatomies that show relative displacement of OAR in close proximity to a tumor target. We formulated an efficient genetic algorithm which makes it possible to search for global minima in a complex landscape of multiple irradiation strategies delivering a given, predetermined intensity map to a target. The optimal strategy was investigated with respect to minimizing the dose delivered to the OAR. The optimization procedure developed relies on variability of all parameters available for control of radiation delivery in modern linear accelerators, including adaptation of leaf trajectories and simultaneous modification of beam dose rate during irradiation. We showed that the optimization algorithms lead to a significant reduction in the dose delivered to OAR in cases where organs at risk move relative to a treatment target.

Optical control of DNA base radio sensitivity.

We describe manipulation of the radio sensitivity of the nucleotide base driven by the spin blockade mechanism of diffusive free radicals against ionizing radiation. We theoretically propose a mechanism which uses the simultaneous application of circularly polarized light and an external magnetic field to control the polarization of the free radicals and create S=1 electron-hole spin excitations (excitons) on a nucleotide base. We deploy an ab initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions. As a specific example, we present the numerical results calculated for a guanine in the presence of an OH free radical. To increase the radio resistivity of this system, an energy gap for the optical pumping and induction of excitons on guanine is predicted. The effect of spin injection on the formation of a free energy barrier in diffusion-controlled chemical reaction pathways leads to the control of radiation-induced base damage. The proposed method allows us to manipulate and partially suppress the damage induced by ionizing radiation.

Piezomagnetic quantum dots.

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.

Variable beam dose rate and DMLC IMRT to moving body anatomy.

Derivation of formulas relating leaf speeds and beam dose rates for delivering planned intensity profiles to static and moving targets in dynamic multileaf collimator (DMLC) intensity modulated radiation therapy (IMRT) is presented. The analysis of equations determining algorithms for DMLC IMRT delivery under a variable beam dose rate reveals a multitude of possible delivery strategies for a given intensity map and for any given target motion patterns. From among all equivalent delivery strategies for DMLC IMRT treatments specific subclasses of strategies can be selected to provide deliveries that are particularly suitable for clinical applications providing existing delivery devices are used. Special attention is devoted to the subclass of beam dose rate variable DMLC delivery strategies to moving body anatomy that generalize existing techniques of such deliveries in Varian DMLC irradiation methodology to static body anatomy. Few examples of deliveries from this subclass of DMLC IMRT irradiations are investigated to illustrate the principle and show practical benefits of proposed techniques.

Tailoring magnetism in quantum dots.

We study magnetism in magnetically doped quantum dots as a function of the confining potential, particle numbers, temperature, and strength of the Coulomb interactions. We explore the possibility of tailoring magnetism by controlling the nonparabolicity of the confinement potential and 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 persists 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 the Coulomb interactions. We predict a series of electronic spin transitions which arise from the competition between the many-body gap and magnetic thermal fluctuations.

Quantum Hall ferrimagnetism in lateral quantum dot molecules.

We demonstrate the existence of ferrimagnetic and ferromagnetic phases in a spin phase diagram of coupled lateral quantum dot molecules in the quantum Hall regime. The spin phase diagram is determined from the Hartree-Fock configuration interaction method as a function of electron number N and magnetic field B. The quantum Hall ferrimagnetic phase corresponds to spatially imbalanced spin droplets resulting from strong interdot coupling of identical dots. The quantum Hall ferromagnetic phases correspond to ferromagnetic coupling of spin polarization at filling factors between nu=2 and nu=1.

Real space Hartree-Fock configuration interaction method for complex lateral quantum dot molecules.

We present unrestricted Hartree-Fock method coupled with configuration interaction (CI) method (URHF-CI) suitable for the calculation of ground and excited states of large number of electrons localized by complex gate potentials in quasi-two-dimensional quantum dot molecules. The method employs real space finite difference method, incorporating strong magnetic field, for calculating single particle states. The Hartree-Fock method is employed for the calculation of direct and exchange interaction contributions to the ground state energy. The effects of correlations are included in energies and directly in the many-particle wave functions via CI method using a limited set of excitations above the Fermi level. The URHF-CI method and its performance are illustrated on the example of ten electrons confined in a two-dimensional quantum dot molecule.