Computational Studies of Ion-Induced Water Radiolysis and DNA Damage

质子癌症治疗（PCT）使用高能质子杀死癌性肿瘤，对肿瘤细胞的损伤最小。 健康的组织，没有X射线治疗的副作用。碰撞质子诱导细胞水辐解 产生活性物质的反应：离子、电子和自由基。这些物种会破坏 癌细胞，促进其凋亡。尽管已建立临床应用，PCT的微观细节 反应仍然难以捉摸。这阻碍了PCT的合理设计，使其治疗能力最大化 尽量减少副作用PCT的这种不佳特征是由于即使是最先进的 实验/临床技术不能完全揭示PCT的微观细节，特别是在没有 伤害人类实验对象为了克服这种情况，我们正在进行PCT反应的计算机模拟 用新颖的量子动力学方法。因此，不能安全测试的危险PCT反应， 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-一个时间依赖的，可变的，在飞行和非- 绝热方法-在我们的并行代码PACE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-细胞水中的基本PCT反应， 和损伤细胞DNA的自由基;（2）质子诱导的DNA损伤和（3）电子诱导的DNA损伤。 对于（3），我们将验证Simons的电子诱导DNA损伤机制（DNA碱基中的电子捕获， 通过糖转移，以及磷酸酯键处的单链断裂）和其它竞争机制 最近的DNA实验显示。我们是第一个执行时间相关的，非绝热模拟的， 用于反应（2）和（3）的大的核苷酸样品。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反应机理的精确测定 以及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、放射治疗疗程、辐射防护方案的蒙特卡罗（MC）代码 和医学成像（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，我们的研究正在对PCT研究和治疗以及其他离子领域产生积极影响。 诱导DNA损伤的研究，如非癌放疗，诱变研究，衰老等，我们 将使用现有的和新的END方法。现有的方法是最简单的END和我们的END/Kohn- 伪密度泛函理论，包括电子相关效应。这两种方法都采用核经典 力学和电子单行列式波函数。利用这笔赠款开发的新方法 用连续极化模型描述溶剂化效应对PCT反应的影响 水，和END与平面波，以准确地描述散射/捕获的未结合的电子从水/ DNA.有了这些新方法，计算机设备行动伙伴关系将成为描述PCT程序的更准确和更通用的工具。

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.