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

这项拟议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DNA中包含的遗传信息可能会受到外部和内部影响（例如，紫外线、污染物和激素）的破坏。虽然我们细胞中的酶可以修复这种损伤，但一些损伤会持续存在，并对健康产生重大影响（例如，癌症、炎症性疾病和自身免疫性疾病）。这项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有力预测者，澄清实验假设和结果之间的差异，并提供传统湿法实验无法获得的信息。提出的研究是独特的基于明智地使用一系列计算方法和密切磋商与领先的实验。

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.