DYNAMIC SIMULATIONS OF RADIATION DAMAGE TO DNA

这项提议的长期目标是开发一种分子 从基本原则中得出的对桥梁阶段的理解 在DNA环境中的高能沉积和 发展出永久性受损的DNA。以下提出的计划侧重于 关于间接损害的化学，定义为相互作用 DNA和在其环境中产生的活性物种。在工作中 该提案的假设是间接损害受费率控制。 活性物种与DNA之间的反应常数。这些 速率常数取决于活性物种和活性物质之间的碰撞。 DNA，关于随后的化学反应的速度，以及关于 清除这些激进分子。此外，DNA的动态结构具有 对总产量和间接损害率有重要影响。我们 将使用专门设计的理论方法的组合 解决提案每一节中的具体问题。 第一部分是对碰撞事件的描述。 DNA的活性颗粒和成分(例如，碱基、糖和 核苷酸)以及单链和双链DNA的模型。vbl.使用 布朗动力学模拟，我们计划计算速率常数和 扩散控制碰撞的统计分布由 DNA和活性粒子之间的长程作用力。第二 这一节讨论的是那些由 化学键的断裂和形成(例如，碱上的OH加成和H- 用羟基从糖中提取)。这些反应的速率常数为 由扩散控制的碰撞和效率组成 由障碍物决定的化学事件。能量障碍 这些反应将用量子化学方法进行计算。在……里面 第三部分，我们建议构建一个完整的表示 活性物种与动态波动的DNA的相互作用。 布朗动力学模拟和量子化学研究的结果 将由分子动力学模拟来补充，以提供 反应物之间碰撞和相互作用的综合描述 颗粒和动态活跃的DNA。这些研究，除了 提供DNA中初始损伤的分布速度和概率， 将成为评价的重要理论基础 氧在损害“修复”和清道夫在提供防护方面的作用 对DNA的间接损伤。

The long term goal of this proposal is to develop a molecular understanding, derived from first principles, of the stages that bridge between the deposition of high energy in the environment of DNA and the development of permanently damaged DNA. The plan presented below focuses on the chemistry of the indirect damage, defined as the interaction between DNA and the reactive species produced in its environment. The working hypothesis of the proposal is that indirect damage is controlled by rate constants of the reactions between the reactive species and DNA. These rate constants depend on the collision between the reactive species and DNA, on the rates of subsequent chemical reactions, and on the rates of scavenging of these radicals. Also, the dynamic structure of DNA has an important influence on the overall yield and rates of indirect damage. We will use a combination of theoretical methods which are especially designed to address the specific problems in each of the sections of the proposal. The first deals with the characterization of the collision event between reactive particles and components of DNA (e.g., bases, sugars, and nucleotides) as well as models of single and double stranded DNA. Using Brownian dynamics simulations we plan to compute the rate constants and statistical distribution of diffusion controlled collisions determined by long range forces between DNA and the reactive particles. The second section deals with those bimolecular reactions that are governed by breakage and formation of chemical bonds (e.g., OH addition to bases and H- abstraction from sugar by OH). The rate constants for these reactions are composed from the diffusion controlled collisions and from the efficiency of the chemical event determined by the barriers. The energetic barriers for these reactions will be calculated with quantum chemical methods. In the third section we propose to construct an integrated representation of the interaction of the reactive species with dynamically fluctuating DNA. Results from Brownian dynamics simulations and quantum chemical studies will be supplemented by Molecular dynamics simulations to provide an integrated description of collisions and interactions between reactive particles and dynamically active DNA. These studies, in addition to providing rates and probabilities of distribution of initial damage in DNA, will become the theoretical basis for the evaluation f the importance of oxygen in damage "fixing" and of scavengers in providing protection against indirect damage to DNA.