Computational Studies of Ion-Induced Water Radiolysis and DNA Damage

离子诱导水辐射分解和 DNA 损伤的计算研究

• 批准号: 9813409
• 负责人: Jorge Alberto Morales
• 金额: $ 44.08万
• 依托单位: TEXAS TECH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813409
• 关键词: Adopted; Aging; Apoptosis; Area; Attention; Biological Response Modifier Therapy; Breast; Cancerous; Cells; Classical Mechanics; Clinical; Code; Computer Simulation; Computers; DNA; DNA Damage; DNA Single Strand Break; Dangerousness; Data; Development; Electron Transport; Electrons; Esters; Eye; Grant; Head and neck structure; Human body; Investigation; Ions; Lung; Malignant Neoplasms; Medical Imaging; Methods; Microscopic; Modeling; Mutagenesis; Names; Nuclear; Nucleotides; Outcome; Process; Property; Prostate; Protocols documentation; Protons; Radiation Protection; Radiation therapy; Radiometry; Reaction; Research; Research Project Grants; Running; Sampling; Site; Solvents; System; Techniques; Testing; Therapeutic; Therapeutic Studies; Time; Tissues; Variant; Water; X-Ray Therapy; base; cancer therapy; cell water; computer studies; cost; density; design; experimental study; human subject; improved; ionization; method development; novel; prevent; proton therapy; prototype; quantum; side effect; simulation; sugar; theories; tool; tumor; vibration; virtual; weapons

Proton cancer therapy (PCT) uses high-energy protons to kill cancerous tumors with minimum damage on healthy tissues and without the side effects of X-ray therapy. Colliding protons induce cell water radiolysis reactions that generate reactive species: ions, electrons and radicals. Those species damage the DNA of cancerous cells, prompting their apoptosis. Despite established clinical use, the microscopic details of PCT reactions remain elusive. That has prevented a rational design of PCT that can maximize its therapeutic power and minimize its side effects. This poor characterization of PCT is due to the fact that even the most advanced experimental/clinical techniques cannot completely reveal the microscopic details of PCT, especially without harming human subjects. To overcome this situation, we are conducting computer simulations of PCT reactions with novel quantum-dynamics methods. Thus, dangerous PCT reactions that cannot be safely tested in the human body are innocuously run on computers at a very low cost. Our proposed quantum-dynamics methods are based on the electron nuclear dynamics (END) theory —a time-dependent, variational, on-the-fly and non- adiabatic method— implemented in our parallel code PACE. We will study three main types of PCT reactions: (1) PCT water radiolysis reactions—the fundamental PCT reactions in cell water that produce the ions, electrons and radicals that damage cellular DNA; (2) proton-induced DNA damage and (3) electron-induced DNA damage. For (3), we will verify Simons' mechanism for electron-induced DNA damage (electron capture in a DNA base, transfer through sugar, and single strand break at the phospho-ester bond) and other competing mechanisms revealed by recent DNA experiments. We are the first performing time-dependent, non-adiabatic simulations of large nucleotide samples for reactions (2) and (3). Our studies will provide results not obtained before by other computer simulations and experiments, such as the precise determination of the mechanisms of PCT reactions and the accurate prediction of reactions integral cross sections. Those cross sections are the needed input data to design Monte Carlo (MC) codes used for radiation dosimetry, radiotherapy sessions, radioprotection protocols and medical imaging (the team of the MC code TILDA-V has paid attention to some of our results in their designs). Thus, our studies are making a positive impact on PCT research and therapeutics and on other areas of ion- induced DNA damage research such as non-cancerous radiotherapy, studies of mutagenesis, ageing, etc. We will use both existing and new END methods. Existing methods are the simplest-level END and our END/Kohn- Sham Density Functional Theory that includes electron correlation effects. Both methods adopt nuclear classical mechanics and an electronic single-determinantal wavefunction. New methods to be developed with this grant are END with the continuum polarizable model, to describe the solvation effects on PCT reactions by cell bulk water, and END with plane waves, to accurately describe scattering/capture of unbound electrons from water/to DNA. With these new methods, PACE will become a more accurate and versatile tool to describe PCT processes.

质子癌症治疗(PCT)使用高能质子以最小的损害杀死癌症肿瘤 健康的组织，没有X射线治疗的副作用。质子碰撞引起细胞水辐射分解 产生活性物质的反应：离子、电子和自由基。这些物种破坏了人类的DNA 癌细胞，促进它们的凋亡。尽管已有临床应用，但PCT的微观细节 反应仍然难以捉摸。这阻碍了PCT的合理设计，使其能够最大限度地发挥其治疗效果 并将其副作用降至最低。这种对PCT的糟糕描述是由于这样一个事实，即使是最先进的 实验/临床技术不能完全揭示PCT的微观细节，特别是在没有 伤害人类受试者。为了克服这种情况，我们正在进行PCT反应的计算机模拟 用新的量子动力学方法。因此，危险的PCT反应不能在 人体以非常低的成本在计算机上无害地运行。我们提出的量子动力学方法 是基于电子核动力学(END)理论--一种依赖时间的、变分的、动态的和非动态的理论. 绝热方法--在我们的并行代码中实现。我们将研究三种主要类型的PCT反应： (1)PCT水辐解反应--细胞水中产生离子、电子的基本PCT反应 以及破坏细胞DNA的自由基；(2)质子诱导的DNA损伤；(3)电子诱导的DNA损伤。 对于(3)，我们将验证Simons的电子诱导DNA损伤的机制(DNA碱基中的电子捕获， 通过糖转移，单链在磷酸酯键处断裂)和其他竞争机制 最近的DNA实验揭示了。我们是第一个执行与时间相关的、非绝热模拟的 用于反应(2)和(3)的大核苷酸样本。我们的研究将提供其他人以前没有得到的结果 计算机模拟和实验，如PCT反应机理的精确确定 反应积分截面的准确预测。这些横截面是所需的输入数据 设计用于辐射剂量测定、放射治疗过程、辐射防护方案的蒙特卡罗(MC)代码 医学成像(MC代码Tilda-V的团队在他们的设计中注意到了我们的一些结果)。 因此，我们的研究对PCT的研究和治疗以及离子的其他领域都产生了积极的影响。 诱发DNA损伤的研究，如非癌性放射治疗、诱变、衰老等研究 将同时使用现有和新的End方法。现有的方法是最简单的目的和我们的目的/科恩- 包含电子相关效应的伪密度泛函理论。这两种方法都采用了核经典 力学和电子单行列式波函数。利用这笔赠款将开发新的方法 最后用连续介质极化模型来描述溶剂化对PCT反应的影响 水，并以平面波结束，以准确地描述自由电子从水/TO的散射/捕获 DNA有了这些新的方法，PACE将成为描述PCT过程的更准确和更通用的工具。