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

这项拟议的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因暴露在外部和内部影响(例如紫外线、污染物和激素)而受到破坏。尽管我们细胞中的酶可以修复这种损伤，但一些损伤仍然存在，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。高精度的计算机计算可以作为实验结果的强大预测因子，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提供的信息。这项拟议的研究独特地基于对一系列计算方法的明智使用，并与领先的实验者进行了密切的磋商。 首先，拟议的工作将侧重于多种来源(杀虫剂、烟草、石油)产生的致癌物与DNA直接作用时形成的DNA加合物。这些加合物被认为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旨在对抗DNA加合物影响的研究是必要的。具体地说，计算将绘制化学成分如何影响加合物形成途径和细胞处理，包括复制DNA以进行细胞分裂(DNA复制)和蛋白质合成(DNA转录)。其次，拟议的研究将解决目前悬而未决的问题，即核苷酸(NER)和碱基(BER)切除修复这两个关键DNA修复过程中涉及的酶修复的速度(催化效率)和损伤类型(选择性)。最初，将对受损DNA和修复酶之间的相互作用进行建模，以揭示对识别DNA损伤至关重要的结构特征。随后，将使用先进的技术来了解许多酶在每个修复过程中所采用的化学步骤。 由于我们越来越多地暴露在环境中的有害物质中，研究DNA损伤和修复极其重要。尽管需要计算来补充和解释实验数据，但这些数据往往缺乏直接的结构细节，或者收集起来非常耗时，但计算建模在这一领域的使用是有限的。拟议中的研究将立即对化学和生物学产生影响，2015年诺贝尔化学奖授予那些发现了关键DNA修复途径的人就突显了这一点。从长远来看，拟议的工作将发现新的化学物质，这些化学物质将有助于开发抗击人类疾病的新型诊断分析或药物，或设计基于修饰DNA结构的创新材料。

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.