Xie Yixin, Karki Chitra B, Chen Jiawei, Liu Dongfang, Li Lin
Computational Science Program, University of Texas at El Paso, El Paso, TX, United States.
Computer Science Program, Santa Monica College, Santa Monica, CA, United States.
Front Mol Biosci. 2021 Aug 6;8:718587. doi: 10.3389/fmolb.2021.718587. eCollection 2021.
Uracil-DNA glycosylase (UDG) is one of the most important base excision repair (BER) enzymes involved in the repair of uracil-induced DNA lesion by removing uracil from the damaged DNA. Uracil in DNA may occur due to cytosine deamination or deoxy uridine monophosphate (dUMP) residue misincorporation during DNA synthesis. Medical evidences show that an abnormal expression of UDG is related to different types of cancer, including colorectal cancer, lung cancer, and liver cancer. Therefore, the research of UDG is crucial in cancer treatment and prevention as well as other clinical activities. Here we applied multiple computational methods to study UDG in several perspectives: Understanding the stability of the UDG enzyme in different pH conditions; studying the differences in charge distribution between the pocket side and non-pocket side of UDG; analyzing the field line distribution at the interfacial area between UDG and DNA; and performing electrostatic binding force analyses of the special region of UDG (pocket area) and the target DNA base (uracil) as well as investigating the charged residues on the UDG binding pocket and binding interface. Our results show that the whole UDG binding interface, and not the UDG binding pocket area alone, provides the binding attractive force to the damaged DNA at the uracil base.
尿嘧啶-DNA糖基化酶（UDG）是碱基切除修复（BER）中最重要的酶之一，它通过从受损DNA中去除尿嘧啶来修复尿嘧啶诱导的DNA损伤。DNA中的尿嘧啶可能由于胞嘧啶脱氨或DNA合成过程中脱氧尿苷单磷酸（dUMP）残基错掺入而产生。医学证据表明，UDG的异常表达与不同类型的癌症有关，包括结直肠癌、肺癌和肝癌。因此，对UDG的研究在癌症治疗、预防以及其他临床活动中至关重要。在此，我们应用多种计算方法从多个角度研究UDG：了解UDG酶在不同pH条件下的稳定性；研究UDG口袋侧和非口袋侧电荷分布的差异；分析UDG与DNA界面区域的场线分布；对UDG的特殊区域（口袋区域）和目标DNA碱基（尿嘧啶）进行静电结合力分析，并研究UDG结合口袋和结合界面上的带电残基。我们的结果表明，整个UDG结合界面，而不仅仅是UDG结合口袋区域，为尿嘧啶碱基处的受损DNA提供了结合吸引力。
