Computaional study of DNA repair enzyme photolyase

光解酶是一种DNA修复酶，它通过光解酶辅酶FADH-与DNA二聚体之间的光诱导电子转移，将紫外线损伤的DNA中的胸腺嘧啶二聚体裂解。最近，DNA/光解酶复合体的晶体结构被解决，证实了早期的预测，即当酶结合时，DNA局部融化，二聚体从DNA螺旋翻转出来，在三埃距离内接近FADH辅因子。光解酶/DNA复合体的可分辨结构，加上最先进的计算机模拟，为在原子尺度上深入了解细胞维持其基因组稳定的一些关键机制提供了一个独特的机会。基于最新的X射线结构数据和以前的模型，利用早期开发的先进计算技术，该小组将研究光解酶对胸腺嘧啶二聚体进行光修复的不同方面。具体目标包括研究酶FADH氧化还原辅助因子和DNA胸腺嘧啶二聚体之间的电子转移机制；修复反应本身，其中二聚体分裂；光解酶在DNA上发现二聚体的机制；以及二聚体在络合物形成和二聚体识别过程中翻转出DNA螺旋的机制。计算机模拟在生物发现过程中发挥着越来越大的作用。由于该项目的主题横跨癌症、细胞衰老、基因调控、生物节律和分子进化等领域，该项目中的计算研究为参与这项工作的博士后、研究生和本科生团队提供了非常丰富的培训基础。

Photolyase is a DNA repair enzyme, which splits thymine dimers in UV-damaged DNA by photoinduced electron transfer between photolyase cofactor FADH- and the dimer of DNA. Recently, the crystal structure of the DNA/Photolyase complex has been solved, confirming an earlier prediction that upon the enzyme binding, DNA locally melts, the dimer flips out of the DNA helix and approaches the FADH cofactor within a three- angstrom distance. The resolved structure of the photolyase/DNA complex, together with state-of-the-art computer simulations, open up a unique opportunity to gain atomic-scale insights into some of the key mechanisms by which cells maintains stability of their genomes. Building upon the most recent X-ray structural data and previous modeling, using advanced computational techniques developed earlier, the group will investigate different aspects of photorepair of thymine dimers by photolyase. Specific aims include a study of the mechanism of electron transfer between the enzyme FADH redox co-factor and the thymine dimer of DNA; the repair reaction itself, in which the dimer splits; the mechanism by which photolyase finds the dimer on DNA; and the mechanism by which the dimer flips out of the DNA helix in the process of complex formation and dimer recognition. Computer simulations play an ever increasing role in the process of biological discovery. As the themes of the project cut across such areas as cancer, cell aging, gene regulation, biological rhythms, and molecular evolution, the computational research in this project provides an exceptionally rich training ground for a team of a postdoc, grad student, and an undergraduate involved in this work.