The information contained within DNA as a sequence of nucleobases is required for life of most organisms, yet can get altered when the nucleobases are damaged upon exposure to many internal (hormones) and external (ultraviolet sunlight, pollutants) sources. As a result, repair pathways exist to combat the potentially detrimental effects of DNA damage. Nonbulky nucleobase damage (nucleobase oxidation, alkylation and deamination) is commonly removed by the base excision repair (BER) pathway, which involves several enzymes. The first BER enzymes are the DNA glycosylases, which are responsible for identifying the damaged base, flipping the base into the enzyme active site and removing the damaged nucleobase from the sugar–phosphate backbone. Due to the stability of many forms of damaged DNA, the DNA glycosylases must achieve great catalytic power. Understanding the mechanistic details associated with DNA glycosylases is essential for developing detection and treatment strategies for many diseases as abnormal glycosylase function has been associated with cancers, metabolic dysfunctions, neurodegeneration and epigenetic programming during embryo development. Molecular level insight into the function of a wide range of DNA glycosylases has been obtained from computational chemistry, including quantum mechanical cluster calculations, combined quantum mechanics‐molecular mechanics approaches and molecular dynamics simulations. By discussing some of the modeling that has been performed to date on monofunctional DNA glycosylases, the key contributions of the field of computational chemistry to broadening our understanding of the function of this important enzyme family, as well as the critical interplay between traditional biochemical experiments and computer calculations, is highlighted.

中文翻译：

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DNA修复的计算研究：洞察单功能DNA糖基化酶在碱基切除修复途径中的功能

DNA中包含的作为核碱基序列的信息是大多数生物体生命所必需的，但是当这些核碱基暴露于许多内部（激素）和外部（紫外线，污染物）源后遭到破坏时，该信息可能会改变。结果，存在修复途径来对抗DNA损伤的潜在有害作用。通常通过碱基切除修复（BER）途径消除非大量的核碱基损伤（核碱基氧化，烷基化和脱氨基），该途径涉及多种酶。第一个BER酶是DNA糖基化酶，负责识别受损的碱基，将碱基翻转到酶的活性位点，并从糖-磷酸盐骨架中除去受损的核碱基。由于多种形式的受损DNA的稳定性，DNA糖基化酶必须具有强大的催化能力。了解与DNA糖基化酶相关的机制细节对于开发多种疾病的检测和治疗策略至关重要，因为异常糖基化酶功能已与胚胎发育过程中的癌症，代谢功能障碍，神经退行性变和表观遗传程序相关。分子水平对广泛的DNA糖基化酶功能的洞察力已从计算化学中获得，包括量子力学簇计算，量子力学-分子力学组合方法和分子动力学模拟。通过讨论迄今为止对单功能DNA糖基化酶进行的一些建模，计算化学领域对拓宽我们对这一重要酶家族功能的理解的关键贡献，