Masson Fanny, Laino Teodoro, Rothlisberger Ursula, Hutter Jürg
Physikalisch Chemisches Institut, Universität Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
Chemphyschem. 2009 Feb 2;10(2):400-10. doi: 10.1002/cphc.200800624.
On the mend: The repair reaction of the thymine dimer by DNA photolyase (see picture) is studied by hybrid quantum mechanical/molecular mechanical dynamics simulations based on the X-ray structure of the enzyme-DNA complex. The dynamics of splitting of the thymine dimer radical anion within the DNA photolyase active site is characterized. The model includes the protein environment. DNA photolyase is a highly efficient light-driven enzyme that repairs the UV-induced cyclobutane pyrimidine dimer in damaged DNA. Herein, we investigate the repair reaction of the thymine dimer by means of hybrid quantum mechanical/molecular mechanical (QM/MM) dynamics simulations based on the X-ray structure of an enzyme-DNA complex. In analogy to the self-repair reaction, we find that the splitting mechanism of the cyclobutane ring is asynchronously concerted and is complete within a few picoseconds upon electron uptake. A few distinct processes characterize the dynamics of splitting of the thymine dimer radical anion within the DNA photolyase active site: continuous solvation reordering of the catalytic region, proton transfer from Glu283 to the dimer, as well as tight interactions of the cationic side chains of Arg232 and Arg350 with the thymine dimer. This points to the important role of the active-site hydrogen bond and salt-bridge patterns in stabilizing the thymine dimer anion and slowing down the electron back-transfer process. Comparison of the repair efficiency with respect to the self-repair reaction is also discussed.
基于酶 - DNA 复合物的 X 射线结构，通过混合量子力学/分子力学动力学模拟研究了 DNA 光解酶对胸腺嘧啶二聚体的修复反应（见图）。对 DNA 光解酶活性位点内胸腺嘧啶二聚体自由基阴离子的分裂动力学进行了表征。该模型包括蛋白质环境。DNA 光解酶是一种高效的光驱动酶，可修复受损 DNA 中紫外线诱导的环丁烷嘧啶二聚体。在此，我们基于酶 - DNA 复合物的 X 射线结构，通过混合量子力学/分子力学（QM/MM）动力学模拟研究胸腺嘧啶二聚体的修复反应。与自我修复反应类似，我们发现环丁烷环的分裂机制是异步协同的，并且在摄取电子后几皮秒内完成。DNA 光解酶活性位点内胸腺嘧啶二聚体自由基阴离子的分裂动力学有几个不同的过程：催化区域的连续溶剂化重排、质子从 Glu283 转移到二聚体，以及 Arg232 和 Arg350 的阳离子侧链与胸腺嘧啶二聚体的紧密相互作用。这表明活性位点氢键和盐桥模式在稳定胸腺嘧啶二聚体阴离子和减缓电子回传过程中起着重要作用。还讨论了与自我修复反应相比的修复效率。
