Radiation damage induced by ion beams is traditionally treated at different levels of theoretical approaches, for the different scales and mechanisms involved.We present here details of a combined approach that, from a method at a nanoscopic scale, attempts to merge with higher scales existing results, by tuning the analytical method employed when extended to larger scale and so yielding a consistent picture of the entire process. Results will show the possibility to get a good agreement with macroscale methods and, on the other hand, to produce a reliable electron energy spectra to be used for DNA damage estimations.
We propose a multi-scale approach to understanding physics related to the ion/proton-beam cancer therapy and calculation of the probability of the DNA damage as a result of irradiation of patients with energetic (up to 430 MeV/u) ions. This approach is inclusive with respect to different scales starting from the long scale defined by the ion stopping followed by a smaller scale defined by secondary electrons and radicals ending with the shortest scale defined by interactions of secondaries with the DNA. We present calculations of the probabilities of single and double strand breaks of the DNA …
Calculations are carried out to determine elastic scattering cross sections and resonance energies for low energy electron impact on uracil and on each of the DNA bases (thymine, cytosine, adenine, guanine), for isolated molecules in their equilibrium geometry. Our calculations are compared with available theory and experiment. We also attempt to correlate this information with experimental dissociation patterns through an analysis of the temporary anion structures that are formed by electron capture in shape resonances.
After irradiation of cancer cells in the ion beam therapy method the concentration of hydrogen peroxide in the cell medium grows significantly. But the role of hydrogen peroxide molecules in cancer treatment has not been determined yet. We assume that interaction of peroxide molecules with DNA atomic groups can block the genetic information of the cancer cell and lead to its neutralization. To understand the possibility of DNA deactivation in the cell, in the present study the formation of complexes of hydrogen peroxide molecules with DNA specific recognition sites (nucleic bases) is considere…
We propose an inclusive approach for calculating characteristics of secondary electrons produced by ions/protons in tissue-like media. This approach is based on an analysis of the projectile's interaction with the medium on the microscopic level. It allows us to obtain the energy spectrum and abundance of secondary electrons as functions of the projectile kinetic energy. The physical information obtained in this analysis is related to biological processes responsible for the irrepearable DNA damage induced by the projectile. In particular, we consider double strand breaks of DNA caused by seco…
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 t…
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 colle…
Ion beam therapy is one of the most progressive methods in cancer treatment. Studies of the water radiolysis process show that the most long-living species that occur in the medium of a biological cell under the action of ionizing irradiation are hydrogen peroxide (H$_2$O$_2$) molecules. But the role of H$_2$O$_2$ molecules in the DNA deactivation of cancer cells in ion beam therapy has not been determined yet. In the present paper, the competitive interaction of hydrogen peroxide and water molecules with atomic groups of non-specific DNA recognition sites (phosphate groups PO$_4$) is investig…
Ion beams have been widely applied in a few biological research fields such as radioactive breeding, health protection, and tumor therapy. Up to now many interesting and impressive achievements in biology and agriculture have been made. Over the past several decades, scientists in biology, physics, and chemistry have pursued investigations focused on understanding the mechanisms of these radiobiological effects of ion beams. From the chemical point of view, these effects are due to the ion irradiation induced biomolecular damage, direct or indirect. In this review, we will present a chemical o…
Due to the physical and chemical processes that are involved, interactions of ionizing radiations with cells lead to single- and double-strand breaks (SSB and DSB) and base damage to DNA cells. The damage may kill the cells or may be mis-repaired and lead to genetic diseases and cancers. Track structure Monte Carlo simulation of the DNA damage provides types of the damage and their frequencies. In the present work, to derive initial DNA damage, we used the Geant4-DNA code to simulate the physical, physico-chemical and chemical stages of interactions of incident beams of 100 eV to 4.5 keV elect…
In our last paper, we have reported the direct interact between energetic ions and DNA, and its components, pointing out that damage to DNA is actually of highest biological consequence, as the integrity of DNA sequence is essential for biological function. Proteins are another kind of important biomolecules. Although much recent attention has been payed to ion irradiation initiated reaction cascades leading to DNA damage, the protein lesions induced by energetic ions remain virtually unexplored at the molecular scale (maybe because there are usually many copies of each protein, so a comparabl…
In this work, we report a novel strategy to construct molecular diodes with a record tunable rectification ratio of as high as 10^6 using oxidatively damaged DNA molecules. Being exposed to several endogenous and exogenous events, DNA suffers constant oxidative damages leading to oxidation of guanine to 8-Oxoguanine (8oxoG). Here, we study the charge migration properties of native and oxidatively damaged DNA using a multiscale multiconfigurational methodology comprising of molecular dynamics, density functional theory and kinetic Monte Carlo simulations. We perform a comprehensive study to und…
The scientific community shows a great interest in the study of DNA damage induction, DNA damage repair and the biological effects on cells and cellular systems after exposure to ionizing radiation. Several in-silico methods have been proposed so far to study these mechanisms using Monte Carlo simulations. This study outlines a Geant4-DNA example application, named "molecularDNA", publicly released in the 11.1 version of Geant4 (December 2022). It was developed for novice Geant4 users and requires only a basic understanding of scripting languages to get started. The example currently proposes …
We propose a multi-scale approach to understand the physics related to ion-beam cancer therapy. It allows the calculation of the probability of DNA damage as a result of irradiation of tissues with energetic ions, up to 430 MeV/u. This approach covers different scales, starting from the large scale, defined by the ion stopping, followed by a smaller scale, defined by secondary electrons and radicals, and ending with the shortest scale, defined by interactions of secondaries with the DNA. We present calculations of the probabilities of single and double strand breaks of DNA, suggest a way to fu…
We present the latest advances of the multiscale approach to radiation damage caused by irradiation of a tissue with energetic ions and report the most recent advances in the calculations of complex DNA damage and the effects of thermal spikes on biomolecules. The multiscale approach aims to quantify the most important physical, chemical, and biological phenomena taking place during and following irradiation with ions and provide a better means for clinically-necessary calculations with adequate accuracy. We suggest a way of quantifying the complex clustered damage, one of the most important f…
Changes in the medium of biological cell nucleus under ion beam action is considered as a possible cause of cell functioning disruption in the living body. As the most long-lived molecular product appeared in the cell after the passage of high energy ions, the hydrogen peroxide molecule is picked out. The possibility of the formation of stable complexes of hydrogen peroxide molecules with active sites of DNA nonspecific recognition (phosphate groups of the double helix backbone) is studied, and the formation of stable DNA-peroxide complexes is considered. Due to the negative charge on the oxyg…
{\bf Purpose}: To develop a first principle and multi-scale model for normal tissue complication probability (NTCP) as a function of dose and LET for proton and in general for particle therapy with a goal of incorporating nano-scale radio-chemical to macro-scale cell biological pathways, spanning from initial DNA damage to tissue late effects. {\bf Methods}: The method is combination of analytical and multi-scale computational steps including (1) derivation of functional dependencies of NTCP on DNA driven cell lethality in nanometer and mapping to dose and LET in millimeter, and (2) 3D-surface…
The interaction of heavy charged particles with DNA is of interest for several areas, from hadrontherapy to aero-space industry. In this paper, a TD-DFT study on the interaction of a 4 keV proton with an isolated DNA base pair was carried out. Ehrenfest dynamics was used to study the evolution of the system during and after the proton impact up to about 193 fs. This time was long enough to observe the dissociation of the target, which occurs between 80-100 fs. The effect of base pair linking to the DNA double helix was emulated by fixing the four O3' atoms responsible for the attachment. The b…
This paper is devoted to the analysis of the complex damage of DNA irradiated by ions. The analysis and assessment of complex damage is important because cells in which it occurs are less likely to survive because the DNA repair mechanisms may not be sufficiently effective. We studied the flux of secondary electrons through the surface of nucleosomes and calculated the radial dose and the distribution of clustered damage around the ion's track. The calculated radial dose distribution is compared to simulations. The radial distribution of the complex damage is found to be different from that of…
Purpose: To present a closed formalism calculating charged particle radiation damage induced in DNA. The formalism is valid for all types of charged particles and due to its closed nature is suited to provide fast conversion of dose to DNA-damage. Methods: The induction of double strand breaks in DNA--strings residing in irradiated cells is quantified using a single particle model. This leads to a proposal to use the cumulative Cauchy distribution to express the mix of high and low LET type damage probability generated by a single particle. A microscopic phenomenological Monte Carlo code is us…
We present a multi-scale simulation of early stage of DNA damages by the indirect action of hydroxyl ($^\bullet$OH) free radicals generated by electrons and protons. The computational method comprises of interfacing the Geant4-DNA Monte Carlo with the ReaxFF molecular dynamics software. A clustering method was employed to map the coordinates of $^\bullet$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 vox…
Although DNA damage is widely viewed as a critical target for the induction of cell killing by ionizing radiation, the exact nature of DNA damage responsible for these effects is unknown. To address this issue, the probability of forming lethal damage by single proton tracks, derived from published survival data for Chinese hamster V79 cells irradiated by protons with energies from 0.57 to 5.01 MeV, has been compared to estimated yields of clustered DNA lesions and repair outcomes calculated with Monte Carlo models. The reported studies provide new information about the potential relationship …
In order to study the molecular damage induced in the form of single-strand and double-strand breaks by the ionizing radiation at the DNA level, Geant4-DNA Monte Carlo simulation code for complete transportation of primary protons and other secondary particles in liquid water have been employed in this work. To this aim, a B-DNA model and a thorough classification of DNA damage concerning their complexity were used. Strand breaks were assumed to have been primarily originated by direct physical interactions via energy depositions, assuming a threshold energy of 17.5 eV, or indirect chemical re…
Therapeutic protons acting on O18-substituted thymidine increase cytotoxicity in radio-resistant human cancer cells. We consider here the physics behind the irradiation during proton beam therapy and diagnosis using O18-enriched thymine in DNA, with attention to the effect of the presence of thymine-18 on cancer cell death.
Single strand breaks are induced in DNA plasmids, pBR322 and pUC19, in aqueous media exposed to strong fields generated using ultrashort laser pulses (820 nm wavelength, 45 fs pulse duration, 1 kHz repetition rate) at intensities of 1-12 TW cm$^{-2}$. The strong fields generate, {\it in situ}, electrons and radicals that induce transformation of supercoiled DNA into relaxed DNA, the extent of which is quantified. Introduction of electron and radical scavengers inhibits DNA damage; results indicate that OH radicals are the primary (but not sole) cause of DNA damage.
The oxidative damage of DNA is a compelling issue in molecular biophysics as it plays a vital role in the epigenetic control of gene expression and is believed to be associated with mutagenesis, carcinogenesis, and ageing. To understand the microscopic structural changes in physical properties of DNA and the resulting influence on its function due to oxidative damage of its nucleotide bases, we have conducted all-atom molecular dynamic simulations of double-stranded DNA (dsDNA) with its guanine bases being oxidized. The guanine bases are more prone to oxidative damage due to the lowest value o…
One of the most progressive methods of cancer treatment is ion beam therapy. The simulations of water radiolysis show that in the cell medium the most long-living species are hydrogen peroxide (H$_2$O$_2$) molecules. But up to the present time the role of H$_2$O$_2$ molecules in the deactivation of cancer cells has not been determined yet. To understand the possible role of H$_2$O$_2$ in ion beam therapy, the competitive interaction of H$_2$O$_2$ and H$_2$O molecules with nucleic bases in a pair on the different stages of genetic information transfer is studied in the present work. Atom-atomic…
Ion-induced DNA damage is an important effect underlying ion-beam cancer therapy. This paper introduces the methodology of modeling DNA damage induced by a shock wave caused by a projectile ion. Specifically, it is demonstrated how single- and double-strand breaks in a DNA molecule could be described by the reactive CHARMM (rCHARMM) force field implemented in the program MBN Explorer. The entire workflow of performing the shock wave simulations, including obtaining the crucial simulation parameters, is described in seven steps. Two exemplary analyses are provided for a case study simulation se…
Using high-quality gas phase electron scattering calculations and multiple scattering theory, we attempt to gain insights on the radiation damage to DNA induced by secondary low-energy electrons in the condensed phase, and to bridge the existing gap with the gas phase theory and experiments. The origin of different resonant features (arising from single molecules or diffraction) is discussed and the calculations are compared to existing experiments in thin films.
In the present work, we develop a general spatial stochastic model to describe the formation and repair of radiation-induced DNA damage. The model is described mathematically as a measure-valued particle-based stochastic system and extends in several directions the model developed in Cordoni et.al. 2021, Cordoni et.al. 2022a, Cordoni et.al. 2022b. In this new spatial formulation, radiation-induced DNA damage in the cell nucleus can undergo different pathways to either repair or lead to cell inactivation. The main novelty of the work is to rigorously define a spatial model that considers the pa…
Understanding the damage of DNA bases from hydrogen abstraction by free OH radicals is of particular importance to reveal the effect of hydroxyl radicals produced by the secondary effect of 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 pre…
According to the experimental evidence damage induced by densely ionizing radiation in mammalian cells is distributed along the DNA molecule in the form of clusters. The most critical constituent of DNA damage are double-strand breaks (DSBs) which are formed when the breaks occur in both DNA strands and are directly opposite or separated by only a few base pairs. The paper discusses a model of clustered DSB formation viewed in terms of compound Poisson process along with the predictive assay of the formalism in application to experimental data.
The radiation-induced damages in bio-molecules are ubiquitous processes in radiotherapy, radio-biology and critical to space-projects. In this study we present a precise quantification of the fragmentation mechanisms of deoxyribonucleic acid (DNA) and the molecules surrounding DNA such as oxygen and water under non-equilibrium conditions using the first-principle calculations based on density functional theory (DFT). Our results reveal the structural stability of DNA-bases and backbone that withstand up to a combined threshold of charge and hydrogen abstraction owing to simultaneous direct and…
{\bf Introduction}: To revisit the formulation of the mean chord length in microdosimetry and replace it by the particle mean free path appropriate for modelings in radio-biology. {\bf Methods}: We perform a collision-by-collision following by event-by-event Geant4 Monte Carlo simulation and calculate double-averaged stepping-length, $\langle\langle l \rangle\rangle$, for a range of target sizes from mm down to $μ$m and depth in water. We consider $\langle\langle l \rangle\rangle$ to represent the particle mean free path. {\bf Results}: We show that $\langle\langle l \rangle\rangle$ continuous…
Single strand breaks are induced in DNA plasmids, pBR322 and pUC19, in aqueous media by intense ultrashort laser pulses (820 nm wavelength, 45 fs pulse duration, 1 kHz repetition rate) at intensities of 1-12 TW cm$^{-2}$. The intense laser radiation generates, {\it in situ}, electrons that induce transformation of supercoiled DNA into relaxed DNA. The extent of electron-mediated relaxation of DNA structure is quantified. Introduction of electron and radical scavengers inhibits DNA damage.
{\bf Purpose}: Manipulation of the radio-sensitivity of the nucleotide-base driven by the spin blockade mechanism of diffusive free radicals against ionizing radiation. {\bf Materials and methods}: 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 nucleotide-base. We deploy an ab-initio molecular dynamics model to calculate the characteristic parameters of the light needed for optical transitions. {\…
A mechanism of double strand breaking (DSB) in DNA due to the action of two electrons is considered. These are the electrons produced in the vicinity of DNA molecules due to ionization of water molecules with a consecutive emission of two electrons, making such a mechanism possible. This effect qualitatively solves a puzzle of large yields of DSBs following irradiation of DNA molecules. The transport of secondary electrons, including the additional electrons, is studied in relation to the assessment of radiation damage due to incident ions. This work is a stage in the inclusion of Auger mechan…
Impact of Oxygen on DNA Damage Distribution in 3D Genome and its Correlation to Oxygen Enhancement Ratio after High-LET Irradiation
Department of Engineering Physics, Tsinghua University（清华大学工程物理系）；Key Laboratory of Particle & Radiation Imaging, Tsinghua University, Ministry of Education（教育部粒子与辐射成像重点实验室）；Institute of Fluid Physics, China Academy of Engineering Physics（中国工程物理研究院流体物理研究所）
We employ a multi-scale mechanistic approach to investigate radiation induced cell toxicities and deactivation mechanisms as a function of linear energy transfer in hadron therapy. Our theoretical model consists of a system of Markov chains in microscopic and macroscopic spatio-temporal landscapes, i.e., stochastic birth-death processes of cells in millimeter-scale colonies that incorporates a coarse-grained driving force to account for microscopic radiation induced damage. The coupling, hence the driving force in this process, stems from a nano-meter scale radiation induced DNA damage that in…
It has been reported that damage of genome in a living cell by ionizing radiation is about one-third direct and two-thirds indirect. The former which has been introduced in our last paper, concerns direct energy deposition and ionizing reactions in the biomolecules; the latter results from radiation induced reactive species (mainly radicals) in the medium (mainly water) surrounding the biomolecules. In this review, a short description of ion implantation induced radical formation in water is presented. Then we summarize the aqueous radical reaction chemistry of DNA, protein and their component…
Dual Photonics Probing of Nano- to Submicron-Scale Structural Alterations in Human Brain Tissues or Cells and Chromatin or DNA with the Progression of Alzheimers Disease
A stochastic agent-based extension of the GSM2 model for particle therapy: cell-cycle dynamics, dose-rate dependence, and fractionation effects
Trento Institute for Fundamental Physics and Application (TIFPA)（特伦托基础物理与应用研究所）；Department of Civil, Environmental and Mechanical Engineering, University of Trento（特伦托大学土木、环境与机械工程系）；Department of Civil and Environmental Engineering, Louisiana State University (LSU)（路易斯安那州立大学土木与环境工程系）；Department of Physics & Astronomy, Louisiana State University (LSU)（路易斯安那州立大学物理与天文系）
DNA double-strand breaks (DSBs) represent a serious source of damage for all living things and thus there have been many quantitative studies of DSBs both in vivo and in vitro. Despite this fact, the processes that lead to their production have not yet been clearly understood, and there is no established theory that can account for the statistics of their production, in particular, the number of DSBs per base pair per unit Gy, here denoted by P1, which is the most important parameter for evaluating the degree of risk posed by DSBs. Here, using the single-molecule observation method with giant …
Gold nanoparticles have been conceived as a radiosensitizer in cancer radiation therapy, but one of the important questions for primary drug screening is what size of gold nanoparticles can optimally enhance radiation effects. Herein, we perform in vitro and in vivo radiosensitization studies of 4.8, 12.1, 27.3, and 46.6 nm PEG-coated gold nanoparticles. In vitro results show that all sizes of the PEG-coated gold nanoparticles can cause a significant decrease in cancer cell survival after gamma radiation. 12.1 and 27.3 nm PEG-coated gold nanoparticles have dispersive distributions in the cells…
The protein p53 has a well established role in protecting genomic integrity in human cells. When DNA is damaged p53 induces the cell cycle arrest to prevent the transmission of the damage to cell progeny, triggers the production of proteins for DNA repair and ultimately calls for apoptosis. In particular, the p53-Mdm2 feedback loop seems to be the key circuit in this response of cells to damage. For many years, based on measurements over populations of cells it was believed that the p53-Mdm2 feedback loop was the responsible for the existence of damped oscillations in the levels of p53 and Mdm…
Low-energy electrons (LEEs) are known to be effective in causing strand breaks in DNA. Recent experiments show that an important direct source of LEEs is the intermolecular Coulombic decay (ICD) process. Here we propose a new cascade mechanism initiated by core excitation and terminated by ICD and demonstrate its properties. Explicit calculations show that the energies of the emitted ICD-electrons can be controlled by selecting the initial atomic excitation. The properties of the cascade may have interesting applications in the fields of electron spectroscopy and radiation damage. Initiating s…
DNA end tethering through break-induced DNA--protein condensation
Max Planck Institute for the Physics of Complex Systems（马克斯·普朗克复杂系统物理研究所）；Technische Universität Dresden（德累斯顿工业大学）；Biotechnology Center, Center for Molecular and Cellular Bioengineering, Technische Universität Dresden（德累斯顿工业大学生物技术中心分子与细胞生物工程中心）；Max Planck Institute of Molecular Cell Biology and Genetics（马克斯·普朗克细胞生物学与遗传学研究所）；Center for Systems Biology Dresden（德累斯顿系统生物学中心）；Cluster of Excellence Physics of Life, Technische Universität Dresden（德累斯顿工业大学“生命物理学”卓越集群）
Low-energy electrons offer a unique possibility for long exposure imaging of individual biomolecules without significant radiation damage. In addition, low-energy electrons exhibit high sensitivity to local potentials and thus can be employed for imaging charges as small as a fraction of one elementary charge. The combination of these properties makes low-energy electrons an exciting tool for imaging charge transport in individual biomolecules. Here we demonstrate the imaging of individual deoxyribonucleic acid (DNA) molecules at the resolution of about 1 nm with simultaneous imaging of the ch…
We develop a kinetic reaction model for cells having irradiated DNA molecules due to ionizing radiation exposure. Our theory simultaneously accounts for the time-dependent reactions of the DNA damage, the DNA mutation, the DNA repair, and the proliferation and apoptosis of cells in a tissue with a minimal set of model parameters. In contrast to existing theories for radiation exposition, we do not assume the relationships between the total dose and the induced mutation frequency. Our theory provides a universal scaling function that reasonably explains the mega-mouse experiments in Ref.[W. L. …
The Geant4-DNA project proposes to develop an open-source simulation software based and fully included in the general-purpose Geant4 Monte Carlo simulation toolkit. The main objective of this software is to simulate biological damages induced by ionising radiation at the cellular and sub-cellular scale. This project was originally initiated by the European Space Agency for the prediction of deleterious effects of radiation that may affect astronauts during future long duration space exploration missions. In this paper, the Geant4-DNA collaboration presents an overview of the whole ongoing proj…
For efficient application of protons and light ions in radiotherapy, detailed knowledge and realistic models of the corresponding radiobiological mechanism are necessary. Basic characteristics of this mechanism have been represented within a probabilistic two-stage model. The processes that occur immediately after the traversals of individual particles and the response of cell to the total damage formed by all the particles have been distinguished. The model involves a probabilistic description of DNA damage formation and repair processes, too.
The present work introduces a rigorous stochastic model, named Generalized Stochastic Microdosimetric Model (GSM2), to describe biological damage induced by ionizing radiation. Starting from microdosimetric spectra of energy deposition in tissue, we derive a master equation describing the time evolution of the probability density function of lethal and potentially lethal DNA damage induced by radiation in a cell nucleus. The resulting probability distribution is not required to satisfy any a priori assumption. Furthermore, we generalized the master equation to consider damage induced by a cont…
Bi, a high atom number element, has a high photoelectric absorption coefficient, and Se element has anticancer activity. Hence, their compound chalcogenide (Bi2Se3) deserves a thorough investigation for biomedical applications. This study reveals that Bi2Se3 nanoplates (54 nm wide) protected with poly(vinylpyrollidone) (PVP) are biocompatible and have low toxicity even at a high dose of 20 mg/kg in mice. This conclusion was made through the studies on the biodistribution and 90-day long term in vivo clearance of the nanoplates. Liver and spleen were dominant organs for the nanoplates accumulat…
