Geant4-DNA simulations using complex DNA geometries generated by the DnaFabric tool

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Abstract

Several DNA representations are used to study radio-induced complex DNA damages depending on the approach and the required level of granularity. Among all approaches, the mechanistic one requires the most resolved DNA models that can go down to atomistic DNA descriptions. The complexity of such DNA models make them hard to modify and adapt in order to take into account different biological conditions. The DnaFabric project was started to provide a tool to generate, visualise and modify such complex DNA models. In the current version of DnaFabric, the models can be exported to the Geant4 code to be used as targets in the Monte Carlo simulation. In this work, the project was used to generate two DNA fibre models corresponding to two DNA compaction levels representing the hetero and the euchromatin. The fibres were imported in a Geant4 application where computations were performed to estimate the influence of the DNA compaction on the amount of calculated DNA damage. The relative difference of the DNA damage computed in the two fibres for the same number of projectiles was found to be constant and equal to 1.3 for the considered primary particles (protons from 300 keV to 50 MeV). However, if only the tracks hitting the DNA target are taken into account, then the relative difference is more important for low energies and decreases to reach zero around 10 MeV. The computations were performed with models that contain up to 18,000 DNA nucleotide pairs. Nevertheless, DnaFabric will be extended to manipulate multi-scale models that go from the molecular to the cellular levels.

Program summary

Program title: DnaFabric

Catalogue identifier: AEZV_v1_0

Program summary URL:http://cpc.cs.qub.ac.uk/summaries/AEZV_v1_0.html

Program obtainable from: CPC Program Library, Queen’s University, Belfast, N. Ireland

Licensing provisions: Apache License, 2.0

No. of lines in distributed program, including test data, etc.: 13514

No. of bytes in distributed program, including test data, etc.: 186753

Distribution format: tar.gz

Programming language: C++.

Computer: Computer with a GPU and OpenGL3.3 compatible drivers.

Operating system: Linux (Ubuntu).

RAM: 4 gigabytes

Classification: 3, 14, 20.

External routines: Qt5 and OpenGL3.3

Nature of problem:

Simulations implying DNA geometrical models often show limitations to support the huge number of DNA constituents. In order to allow users to build, visualise and perform calculations on detailed DNA models including hundreds of thousands of DNA elements, a dedicated framework is needed.

Solution method:

The DnaFabric library is a framework that allows users to easily build their own DNA models, display them and perform calculations. The DnaFabric includes: hierarchically organised DNA models (binary-executable example named “Fibre”), a dedicated 3D render engine, an optimised OpenGL interface and some multi-threading facilities.

Unusual features:

The DnaFabric uses 3D technologies from the computer graphics world allowing the rendering of huge DNA models in real-time.

Additional comments:

Three examples are provided in the Examples folder. The “Basic” example describes how to set-up a simple DnaFabric user-application. The “Fibre” example shows the two DNA fibre models used for the calculations in this paper. The “MovingSpheres” example, demonstrates how to implement a simulation interacting with the DNA geometrical model.

Running time:

Once a user application is started, an auto-generated window will show the 3D model. The efficiency of the rendering depends highly on the user hardware. However, the user can customise each of the rendered elements contained in its application to adjust the required computer power.

Introduction

It is well known that cell inactivation can be initiated by complex DNA damage  [1] created by ionising radiation such as protons, alphas or ions. Therefore, the simulation of a mechanistic approach on the production of such complex DNA damage is an active and multidisciplinary field of research implying physics chemistry and biology where modelling of the DNA target is of major concern. Different representations are used going from very simple models (cylinders)  [2], [3] to extremely refined ones with an atomistic description of the DNA components  [4], [5]. In most of the cases, the models are simplified because they represent a unique chromatin structure. Such models are meant to be used with Monte Carlo (MC) track structure codes that simulate the transport of particles through matter  [4], [6]. However, biology studies demonstrated that DNA is organised within the cell nucleus in a complex manner. At the smallest scale, the atomic structure of the DNA double helix is generally considered as well known but DNA structures of higher levels are describe differently by several models  [7]. This illustrates the need for a tool able to generate flexible DNA geometries to be exported to simulation toolkits such as the Geant4 Monte Carlo (MC) code. Acknowledging the existence of reliable techniques to manipulate 3D objects in the computer graphic field, the DnaFabric project was initiated to manipulate complex DNA geometrical models. Its main objective is the creation of adaptable and complex DNA model. The created DNA models can be exported for in silico calculations. In the current version, an export procedure dedicated to the Geant4 code  [8], [9] has already been implemented. Geant4 is developed by an international collaboration and includes several modelling features which are organised in several packages. The Geant4-DNA  [10], [11] physics within the low energy package are dedicated to the simulation of energy deposition by ionising radiation at nanometric scale for radiobiological applications. Therefore, the DNA geometries created within DnaFabric are directly exported to a suitable form to be used in MC simulations using these Geant4-DNA processes. DnaFabric is divided into several modules each responsible for one of the software capabilities. This architecture was designed to facilitate future modifications and additions by separating the different areas of expertise: graphical user interface (GUI), 3D visualisation, geometrical definitions and deformations. The GUI is the front-end part of the application which is the one interacting with the user. The 3D visualisation implements a real-time rendering system able to display a cell nucleus filled with a hierarchical volume organisation containing 6.109 pairs of nucleotides. The geometrical definition and deformation module includes several tools to ease the construction and edition process of a DNA model.

In this work, a DNA fibre model made of molecular volumes was created with DnaFabric. The molecular level of granularity was chosen to individually identify DNA sugar, phosphate and bases in order to record the DNA localisation of every physical interaction that could be at the origin of a DNA damage. A study about the influence of the DNA compaction level on the resulting DNA damage and their complexity was performed using two DNA geometries made with the dynamic edition tools provided by DnaFabric. Both geometries are presented hereafter.

Section snippets

Overview

The DnaFabric is a C++ software that aims to generate, edit, display and export complex DNA geometrical models from the nucleotide scale to the DNA content of a cell-nucleus. In its current state, the software works with DNA geometrical models of less than 105 volumes and contains a first set of DNA geometrical models as well as tools to manipulate them. Further developments are planned to manage DNA models for the whole human genome that is made of roughly 36.109 volumes if one considers 6

Creation of a DNA geometrical model

The DnaFabric tools presented in Section  2 can be used from scratch to build a new DNA geometrical model or used with DNA models already built in this work to create alternatives using the same structure. The model built and used for calculations (called “DNAMolecular”) is based on a molecular representation of DNA and is dedicated to the study of DNA damage caused by ionising radiations. It describes a straight DNA fibre of about 105 molecules. The geometrical tools included within the

Influence of the compaction level on direct DNA damage

A quantification of the influence of the DNA density at the fibre level on the number of direct energy depositions by ionising radiation is presented in this section in order to illustrate the use of DnaFabric in a practical case. Here, the above presented DNA geometrical models for the heterochromatin and the euchromatin fibres were exported as .dnafab files and, then, loaded in a dedicated Geant4-DNA user application as stated in Section  2.2.2.

Conclusion

DnaFabric has been presented as a new tool aiming to facilitate the creation, edition and visualisation of complex DNA geometries. The geometries can be used within Geant4 to simulate the irradiation of different targets. An application of the project has been shown with the generation of two DNA fibres representing the heterochromatin and euchromatin DNA organisations. A proton irradiation of both geometrical targets was simulated for different energies of the projectile (300 keV–50 MeV) and

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    This paper and its associated computer program are available via the Computer Physics Communication homepage on ScienceDirect (http://www.sciencedirect.com/science/journal/00104655).

    1

    Member of the Geant4-DNA collaboration.

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