Department for Theoretical Chemical Biology, Institute for Physical Chemistry, Karlsruhe Institute for Technology, Kaiserstr. 12, 76131, Karlsruhe, Germany.
Botanical Institute, Karlsruhe Institute of Technology, Fritz Haber Weg 4, 76131, Karlsruhe, Germany.
Phys Chem Chem Phys. 2019 Aug 21;21(31):17072-17081. doi: 10.1039/c9cp01609k. Epub 2019 Jul 17.
The repair of sun-induced DNA lesions by photolyases is driven by a photoinduced electron transfer from a fully reduced FAD to the damaged DNA. A chain of several aromatic residues connecting FAD to solvent ensures the prior photoreduction of the FAD cofactor. In PhrA, a class III CPD photolyase, two branching tryptophan charge transfer pathways have been characterized. According to previous experiments, both pathways play a role in the FAD photoreduction. To provide a molecular insight to the charge transfer abilities of both pathways, we perform multiscales simulations where the protein motion and the positive charge are simultaneously propagated. Our computational approach reveals that one pathway drives a very fast charge transfer whereas the other pathway provides a very good thermodynamic stabilization of the positive charge. During the simulations, the positive charge firstly moves on the fast triad, while a reorganization of the close FAD˙ environment occurs. Then, backward transfers can lead to the propagation of the positive charge on the second pathway. After one nanosecond, we observe a nearly equal probability to find the charge at ending tryptophan of either pathway; eventually the charge distribution will likely evolve towards a charge stabilization on the last tryptophan of the slowest pathway. Our results highlight the role the protein environment, which manages the association of a kinetic and a thermodynamic pathways to trigger a fast and efficient FAD photoreduction.
光解酶通过光诱导电子转移将完全还原的 FAD 转移到受损 DNA 上来修复由阳光引起的 DNA 损伤。连接 FAD 和溶剂的一系列芳香族残基可确保 FAD 辅因子的预先光还原。在 PhrA 类 III CPD 光解酶中，已经确定了两种分支色氨酸电荷转移途径。根据先前的实验，这两种途径都在 FAD 光还原中发挥作用。为了深入了解这两种途径的电荷转移能力，我们进行了多尺度模拟，其中同时传播蛋白质运动和正电荷。我们的计算方法表明，一种途径可以驱动非常快速的电荷转移，而另一种途径可以很好地稳定正电荷。在模拟过程中，正电荷首先沿快速三联体移动，而 FAD˙环境发生重组。然后，反向转移可以导致正电荷在第二途径上传播。经过一纳秒后，我们观察到正电荷几乎有相同的概率位于任一条途径的末端色氨酸上；最终，电荷分布可能会朝着最慢途径的最后一个色氨酸上的电荷稳定方向演变。我们的结果突出了蛋白质环境的作用，该环境管理了动力学和热力学途径的结合，以触发快速有效的 FAD 光还原。
