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

基本信息

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
项目类别：
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

项目摘要

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.

质子癌症疗法 (PCT) 使用高能质子杀死癌性肿瘤，对肿瘤的损害最小健康组织并且没有 X 射线治疗的副作用诱导细胞水辐射分解。产生活性物质的反应：离子、电子和自由基，这些物质会损害 DNA。尽管已在临床上使用，PCT 的微观细节仍然存在。反应仍然难以捉摸，这阻碍了 PCT 的合理设计，以最大限度地发挥其治疗功效。并最大限度地减少 PCT 的不良特征是因为即使是最先进的技术。实验/临床技术无法完全揭示 PCT 的微观细节，尤其是在没有为了克服这种情况，我们正在对 PCT 反应进行计算机模拟。因此，危险的 PCT 反应无法在环境中安全地进行测试。我们提出的量子动力学方法可以以非常低的成本在计算机上无害地运行。基于电子核动力学 (END) 理论——一种依赖于时间的、变分的、动态的和非动态的绝热方法——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水辐射分解反应——细胞水中产生离子、电子的基本PCT反应损伤细胞 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，单链在磷酸酯键处断裂）和其他竞争机制最近的 DNA 实验揭示了这一点，我们是第一个进行时间依赖性、非绝热模拟的人。我们的研究将提供其他研究未获得的结果。计算机模拟和实验，例如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、辐射防护协议的蒙特卡罗 (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损伤研究，如非癌性放射治疗、诱变、衰老研究等。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-。包括电子相关效应的假密度泛函理论两种方法均采用核经典。力学和电子单行列式波函数将利用这笔赠款开发新方法。是连续极化模型的 END，用于描述细胞体积对 PCT 反应的溶剂化作用水，以及平面波 END，以准确描述来自水/到的未结合电子的散射/捕获借助这些新方法，PACE 将成为描述 PCT 流程的更准确、更通用的工具。