Base flipping of the thymine dimer in duplex DNA
Base flipping of the thymine dimer in duplex DNA
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DOI：
10.1021/jp074043e
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发表时间：
2007-10-11
影响因子：
3.3
通讯作者：
Wiest, Olaf
中科院分区：
文献类型：
--
作者：
O'Neil, Lauren L.;Grossfield, Alan;Wiest, Olaf
将DNA中两个相邻的胸腺嘧啶暴露于260-320 nm的紫外光下可导致形成顺式，顺式-环丁烷嘧啶二聚体（CPD）。含有螺旋内CPD损伤的DNA结构先前已经通过实验和计算进行了研究。然而，螺旋外，翻转，CPD病变，这已被证明是结构，结合CPD修复酶，DNA光裂合酶的结构，尚未被报道。在这项工作中的结构翻转和翻转的CPD病变的双链DNA的报告。使用8 ns分子动力学（MD）模拟计算这些结构。然后，这些结构用于定义CPD病变的碱基翻转过程的起点和终点。利用一个复杂的二维伪二面角坐标，采用新的方法计算了基底翻转过程的平均力势。翻转出CPD的自由能比翻转入状态的自由能高大约6.5 kcal/mol，表明CPD的翻转势垒比未受损DNA的翻转势垒低得多。这可能表明翻转的CPD损伤可能被其修复酶DNA光裂合酶识别，而。先前对其它受损和未受损碱基的研究表明，它们在螺旋内翻转状态下被酶识别。
Exposure of two adjacent thymines in DNA to UV light of 260-320 nm can result in the formation of the cis,syn-cyclobutane pyrimidine dimer (CPD). The structure of DNA containing an intrahelical CPD lesion has been previously studied experimentally and computationally. However, the structure of the extrahelical, flipped-out, CPD lesion, which has been shown to be the structure that binds to the CPD repair enzyme, DNA photolyase, has yet to be reported. In this work the structure of both the flipped-in and the flipped-out CPD lesions in duplex DNA is reported. These structures were calculated using 8 ns molecular dynarnics (MD) simulations. These structures are then used to define the starting and ending points for the base-flipping process for the CPD lesion. Using a complex, two-dimensional pseudodihedral coordinate, the potential of mean force (PMF) for the base-flipping process was calculcated using novel methodology. The free energy of the flipped-out CPD is roughly 6.5 kcal/mol higher than that of the flipped-in state, indicating that the barrier to flipping out is much lower for CPD than for undamaged DNA. This may indicate that the flipped-out CPD lesion may be recognized by its repair enzyme, DNA photolyase, whereas. previous studies of other damaged, as well as nondamaged, bases indicate that they are recognized by enzymes in the intrahelical, flipped-in state.