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”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。***首先，拟议的工作将集中于DNA加合物，当多种来源的致癌物（农药，烟草，石油）直接与DNA相互作用时形成的。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，这对于指导未来针对DNA加合物影响的研究是必要的。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，所提出的研究将解决目前尚未解决的问题，即涉及两个关键DNA修复过程的酶，即核苷酸（NER）和碱基（BER）切除修复的速度（催化效率）和损伤修复类型（选择性）。最初，受损DNA和修复酶之间的相互作用将被建模，以揭示对识别DNA损伤至关重要的结构特征。随后，先进的技术将用于了解在每个修复过程中许多酶所采用的化学步骤。由于我们越来越多地接触到环境中的有害物质，研究DNA损伤和修复是非常重要的。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时间限制，计算建模在该领域的使用是有限的。2015年诺贝尔化学奖授予了那些发现关键DNA修复途径的人，这一提议的研究将对化学和生物学产生直接影响。从长远来看，这项工作将发现新的化学物质，这将有助于开发新的诊断分析方法或对抗人类疾病的药物，或基于修改DNA结构的创新材料的设计

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.**