Computaional study of DNA repair enzyme photolyase

光解酶是一种DNA修复酶，通过光解酶辅助因子FADH-与DNA二聚体之间的光诱导电子转移，分裂紫外线损伤DNA中的胸腺嘧啶二聚体。最近，DNA/光解酶复合物的晶体结构已经被解决，证实了早期的预测，在酶结合时，DNA局部融化，二聚体翻转出DNA螺旋并在3埃距离内接近FADH辅因子。光解酶/DNA复合物的解析结构，加上最先进的计算机模拟，为获得原子尺度上的一些关键机制提供了一个独特的机会，通过这些机制，细胞维持其基因组的稳定性。基于最新的x射线结构数据和先前的建模，使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的光修复的不同方面。具体目的包括研究FADH氧化还原辅助因子与DNA胸腺嘧啶二聚体之间的电子转移机制；二聚体分裂的修复反应本身；光解酶在DNA上找到二聚体的机制；以及二聚体在复合体形成和二聚体识别过程中从DNA螺旋中翻转出来的机制。计算机模拟在生物发现过程中起着越来越重要的作用。由于该项目的主题涉及癌症、细胞老化、基因调控、生物节律和分子进化等领域，因此该项目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训练基础。

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.