Multi-Scale Computer Modeling of the Structural Impact and Biochemical Reactions of Damaged DNA

受损 DNA 的结构影响和生化反应的多尺度计算机建模

• 批准号: RGPIN-2016-04568
• 负责人: Wetmore, Stacey
• 金额: $ 5.46万
• 依托单位: University of Lethbridge
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709351
• 关键词: Multi; Scale; Computer; Modeling; Structural

The ultimate goal of the proposed research is to understand how DNA is damaged and repaired in our bodies. The genetic information contained in our DNA can be damaged by exposure to external and internal influences (e.g., UV light, pollutants and hormones). Although enzymes in our cells can repair this damage, some damage persists and has significant health effects (e.g., cancer, inflammatory diseases and autoimmune disorders). The short-term goal of the proposed work is to use computational chemistry to decipher the details of specific DNA damage and repair pathways. Highly accurate computer calculations can serve as powerful predictors of experimental outcomes, clarify discrepancies between experimental hypotheses and results, and provide information not available from traditional wet' experiments. The proposed research is uniquely based on the judicious use of a range of computational approaches and close consultations with leading experimentalists. First, the proposed work will focus on DNA adducts formed when carcinogens arising from many sources (pesticides, tobacco, petroleum) directly interact with DNA. These adducts have been linked to several cancers and other diseases. The proposed research will provide currently missing structure-outcome relationships that are necessary to direct future studies geared towards combating the effects of DNA adducts. Specifically, calculations will map how chemical composition affects adduct formation pathways and cellular processing, including copying DNA for cell division (DNA replication) and synthesis of proteins (DNA transcription). Second, the proposed research will address currently unanswered questions about the speed (catalytic efficiency) and type of damage repaired (selectivity) by enzymes involved in two key DNA repair processes, namely nucleotide (NER) and base (BER) excision repair. Initially, interactions between damaged DNA and repair enzymes will be modeled to reveal structural features that are critical for identifying DNA damage. Subsequently, advanced techniques will be used to understand the chemical steps employed by many enzymes in each repair process. Studying DNA damage and repair is exceedingly important due to our increased exposure to harmful agents in the environment. Despite the necessity of calculations to complement and interpret experimental data, which often lack direct structural details or are time prohibitive to collect, the use of computational modeling in this field is limited. The proposed research will have immediate impact in chemistry and biology, as underscored by the award of the 2015 Nobel Prize in Chemistry to those who identified key DNA repair pathways. In the longer term, the proposed work will uncover new chemistry that will aid the development of novel diagnostic assays or drugs to combat human diseases, or the design of innovative materials based on modified DNA structures.

这项研究的最终目标是了解DNA在我们体内是如何受损和修复的。我们的DNA中包含的遗传信息可能会因暴露于外部和内部影响而受损（例如，紫外线、污染物和激素）。虽然我们细胞中的酶可以修复这种损伤，但有些损伤会持续存在并对健康产生重大影响（例如，癌症、炎性疾病和自身免疫性疾病）。拟议工作的短期目标是使用计算化学来破译特定DNA损伤和修复途径的细节。高度精确的计算机计算可以作为实验结果的强有力的预测器，澄清实验假设和结果之间的差异，并提供传统的湿实验所不能提供的信息。拟议中的研究是唯一的基础上明智地使用一系列的计算方法和密切协商领先的实验。 首先，拟议的工作将集中在DNA加合物形成时产生的致癌物从许多来源（农药，烟草，石油）直接与DNA相互作用。这些加合物与几种癌症和其他疾病有关。拟议的研究将提供目前缺失的结构-结果关系，这些关系对于指导未来的研究对抗DNA加合物的影响是必要的。具体来说，计算将绘制化学成分如何影响加合物形成途径和细胞加工，包括复制DNA进行细胞分裂（DNA复制）和蛋白质合成（DNA转录）。其次，拟议的研究将解决目前尚未回答的问题，即核苷酸（NER）和碱基（BER）切除修复这两个关键DNA修复过程中所涉及的酶修复损伤的速度（催化效率）和类型（选择性）。最初，受损DNA和修复酶之间的相互作用将被建模，以揭示识别DNA损伤的关键结构特征。随后，将使用先进的技术来了解每个修复过程中许多酶所采用的化学步骤。 研究DNA损伤和修复是非常重要的，因为我们越来越多地暴露于环境中的有害物质。尽管计算的必要性，以补充和解释实验数据，这往往缺乏直接的结构细节或时间禁止收集，计算建模在这一领域的使用是有限的。这项研究将对化学和生物学产生直接影响，2015年诺贝尔化学奖授予那些发现关键DNA修复途径的人。从长远来看，拟议的工作将发现新的化学物质，这将有助于开发新的诊断分析或药物来对抗人类疾病，或设计基于修饰的DNA结构的创新材料。