Sato Ryuma, Harada Ryuhei, Shigeta Yasuteru
Center for Computational Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8577, Japan.
Biophys Physicobiol. 2016 Dec 13;13:311-319. doi: 10.2142/biophysico.13.0_311. eCollection 2016.
As for UV-induced DNA damage, which may induce skin cancer in animals and growth inhibition in plants, there are two types of photoproducts, namely cyclobutane pyrimidine dimers (CPD) and pyrimidine-pyrimidone (6-4) photoproducts. When they are to be repaired, base-flipping occurs, and they bind to enzymes. However, this process remains relatively unknown at a molecular level. We analyze conformation and interaction energy changes upon base-flipping using classical molecular dynamics (CMD) simulations and electronic structure calculations. CMD simulations starting with a CPD in the flipped-in and flipped-out states showed that both states were unchanged for 500 ns, indicating the flipped-in and flipped-out processes do not occur spontaneously (without any help of the enzyme) after photo-damage. To deeply understand the reasons, we investigated interaction energy changes among bases upon structure changes during the flipped-in and flipped-out processes using Parallel Cascade Selection-MD (PaCS-MD) simulations at 400 K, followed by a fragment molecular orbital (FMO) method. The total inter-fragment interaction energy (IFIE) between CPD and other bases at the flipped-in state is estimated to be -60.08 kcal/mol. In particular, four bases strongly interact with CPD with interaction energies being -10.96, -13.70, -21.52, and -14.46 kcal/mol each. On the other hand, the total IFIE at the obtained flipped-out state increased to -10.40 kcal/mol by partly losing hydrogen bonds and π-π stacking interactions, respectively. These results clearly indicate that the base-flipping process of DNA lesions occurs with the help of external forces like interactions with appropriate enzymes such as photolyases.
至于紫外线诱导的DNA损伤，它可能在动物中诱发皮肤癌并在植物中抑制生长，有两种光产物，即环丁烷嘧啶二聚体（CPD）和嘧啶 - 嘧啶酮（6 - 4）光产物。当它们需要修复时，碱基翻转发生，并且它们与酶结合。然而，这个过程在分子水平上仍然相对不为人知。我们使用经典分子动力学（CMD）模拟和电子结构计算来分析碱基翻转时的构象和相互作用能变化。从处于翻转入和翻转出状态的CPD开始的CMD模拟表明，这两种状态在500纳秒内都没有变化，这表明光损伤后翻转入和翻转出过程不会自发发生（没有酶的任何帮助）。为了深入理解原因，我们在400 K下使用并行级联选择 - MD（PaCS - MD）模拟，随后采用片段分子轨道（FMO）方法，研究了翻转入和翻转出过程中结构变化时碱基之间的相互作用能变化。在翻转入状态下，CPD与其他碱基之间的总片段间相互作用能（IFIE）估计为 - 60.08千卡/摩尔。特别是，四个碱基与CPD强烈相互作用，相互作用能分别为 - 10.96、 - 13.70、 - 21.52和 - 14.46千卡/摩尔。另一方面，通过分别部分失去氢键和π - π堆积相互作用，在获得的翻转出状态下总IFIE增加到 - 10.40千卡/摩尔。这些结果清楚地表明，DNA损伤的碱基翻转过程是在诸如光解酶等适当酶的相互作用等外力帮助下发生的。
