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 secondary electrons and free radicals, and local heating in the ion's track. The heating may enhance the biological effectiveness of electron/free radical interactions with the DNA and may even be considered as an independent mechanism of DNA damage. Numerical estimates are performed for the case of carbon-ion beams. The obtained dose-depth curves are compared with results of the MCHIT model based on the GEANT4 toolkit.
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 fo…
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.
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 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 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…
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 …
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
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…
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…
{\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…
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…
Published survival data for V79 cells irradiated by monoenergetic protons, helium-3, carbon, and oxygen ions and for CHO cells irradiated by carbon ions have been analyzed using the probabilistic two-stage model of cell inactivation. Three different classes of DNA damages formed by traversing particles have been distinguished, namely severe single-track damages which might lead to cell inactivation directly, less severe damages where cell inactivation is caused by their combinations, and damages of negligible severity that can be repaired easily. Probabilities of single ions to form these dama…
Bone pain typically occurs immediately following skeletal damage with mechanical distortion or rupture of nociceptive fibres. The pain mechanism is also associated with chronic pain conditions where the healing process is impaired. Any load impacting on the area of the fractured bone will increase the intraosseous pressure, consequently stimulating the nociceptive response, necessitating rapid clinical intervention to relieve pain associated with the bone damage and appropriate mitigation of any processes involved with the loss of bone mass, muscle, mobility and, to prevent death. The followin…
The effect of the energy deposition inside the human body made by radioactive substances is discussed. For the first time, we stress the importance of the recoiling nucleus in such reactions, particularly concerning the damage caused on the DNA structure.
Detailed characterization of damage and rupture mechanics of arteries is one the current challenges in vascular biomechanics, which requires developing suitable experimental approaches. This paper introduces an approach using in situ tensile tests in an X-ray micro-tomography setup to observe mechanisms of damage initiation and progression in medial layers of porcine aortic samples. The technique requires the use of sodium polytungstate as a contrast agent, of which the conditions for use are detailed in this paper. Immersion of the samples during 24 hours in a 15 g.L-1 concentrated solution p…
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.
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…
DNA/RNA synthesis precursors are especially vulnerable to damage induced by reactive oxygen species occurring following oxidative stress. Guanosine triphosphates are the prevalent oxidized nucleosites, which can be misincorporated during replication, leading to mutations and cell death. Here, we present a novel method based on micro-Raman spectroscopy, combined with ab initio calculations, for the identification, detection, and quantification of low concentrations of oxidized nucleotides. We also show that the Raman signature in the terahertz spectral range (< 100 cm$^{-1}$) contains informati…
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 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 …
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…
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 …
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…
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…
We propose a mathematical model for estimating biological damage caused by low-dose irradiation. We understand that the Linear Non Threshold (LNT) hypothesis is realized only in the case of no recovery effects. In order to treat the realistic living objects, our model takes into account various types of recovery as well as proliferation mechanism, which may change the resultant damage, especially for the case of lower dose rate irradiation. It turns out that the lower the radiation dose rate, the safer the irradiated system of living object (which is called symbolically "tissue" hereafter) can…
The aim of the present work is spectroscopic and thermodynamic study of DNA catalytic properties in the following processes: a) redox; b) formation of inter-strand cross-links; c) performing of photo-dynamic effects; d) nanoscale resonance radiationless electron excitation energy transfer. The most attention is paid to the latter, as truly nanoscale method in its origin. The nanoscale method of laser induced fluorescence resonance energy transfer (FRET) to donor (acridine orange) - acceptor (ethidium bromide) intercalator pair for quantitative and qualitative study of stability quality DNA dou…
Real time laser induced fluorescence spectroscopy usage for microanalysis of DNA double helix defects is shown. The method is based on Forster resonance energy transfer (FRET) in intercalator-donor pair (acridine orange as a donor and ethidium bromide as an acceptor). Transition metal ions such as Cu(II), Cu(I), Ag(I), silver nanoparticles (AgNPs), photo- and thermo effects were used to cause double helix defects in DNA. FRET radii were experimentally estimated in background electrolyte solution (0.01 M NaNO3) and proved to be 3.9 +- 0.3 nm and the data are in satisfactory agreement with the t…
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）
Tissue engineering technology and tissue cell-based stem cell research have made great strides in treating tissue and organ damage, correcting tissue and organ dysfunction, and reducing surgical complications. In the past, traditional methods have used biological substitutes for tissue repair materials, while tissue engineering technology has focused on merging sperm cells with biological materials to form biological tissues with the same structure and function as their own tissues. The advantage is that tissue engineering technology can overcome donors. Material procurement restrictions can e…
DNA is an essential molecule central to the survival and propagation of life, it was imperative to investigate possible electromagnetic properties inherent to it, such as the existence of any non-trivial interactions of this molecule with electromagnetic fields (beyond the usual dielectric response and damage by ionizing gamma radiations). Extensive investigations were carried out with both prokaryotic and eukaryotic purified DNA samples utilizing some of the most sensitive and precision instrumentation and methods available, while scanning the whole spectral region from 1Hz to 100KHz (in the …
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…
Radiotherapy is often the most straightforward first line cancer treatment for solid tumors. While it is highly effective against tumors, there is also collateral damage to healthy proximal tissues especially with high doses. The use of radiosensitizers is an effective way to boost the killing efficacy of radiotherapy against the tumor while drastically limiting the received dose and reducing the possible damage to normal tissues. Here, we report the design and application of a good radiosensitizer by using ultrasmall gold nanoclusters with a naturally occurring peptide (e.g., glutathione or G…
We present a method for the measurements of the tetrahertz (THz) resonance response of DNA oligonucleotides deposited on a silicon nanosandwich (SNS). It is shown that the SNS device can be used to generate a THz resonance response within living biotissue. The technique we propose measures changes of the longitudinal conductance and the lateral voltage with the SNS device in a Hall geometry. The mechanism of the THz response is discussed, with a model of the generation of Shapiro steps. The THz resonance response from living biotissues will aid the diagnosis of oncological disease and, in gene…
