D,L-[Ru(phen)_2dppz]^(2+)对含G:T错配的环丁烷嘧啶二聚体识别和修复的理论研究

Theoretical study on the recognition and partial structural repair of cyclobutane pyrimidine dimer including double G∶T mismatched pairs by D,L-Ru(phen)_2 dppz^(2+)

环丁烷嘧啶二聚体(Cyclobutane Pyrimidine Dimer,CPD)是紫外线对DNA损伤导致皮肤癌的首要环节,XPC-hHR23B是最早作为对CPD的损伤识别剂的,但其识别效率很低.首次采用分子力学方法模拟了手性金属配合物D,L-[Ru(phen)2dppz]2+(phen=1,10phenanthroline,dppz=dipyrido[3,2-a∶2’,3’-c]phenazine)对含G∶T错配的CPD双螺旋DNA的识别作用.模拟结果显示:该配合物的左手异构体优先从小沟方向识别与G∶T错配相邻的A4T5/T7G6区域,而右手异构体则优先从大沟方向识别与G∶T错配相邻的另一区域T6A7/G5T4.由于CPD的形成,该DNA螺旋高度扭曲,使得识别过程体现了手性选择性和位点特异性,左手异构体更占优势.详细的能量分析发现:在配合物插入碱基堆积过程中的空间位阻状况决定了识别作用的结果,静电相互作用也在一定程度上产生了影响.此外,我们还发现,金属配合物插入CPD相邻的区域后,能将形成CPD的两个T碱基由原来的敞口形状部分地转为近平行状,使其得到构型上的部分修复.

The cyclobutane pyrimidine dimer （CPD） is the chief tache when ultraviolet ray damages DNA that could lead to skin cancer. XPC-hHR23B complex was used as the initial recognition complex of CPD. But its recognition efficiency was very low. This article firstly studied on the recognition of the chiral metal complex D,L-[Ru（phen）2 dppz]^2＋ （phen= 1,10 phenanthroline, dppz = dipyrido [3,2-a ： 2＇, 3＇-c]phenazine） to CPD double helix DNA including double G ： T mismatched pairs by mo- lecular modeling. The results revealed that the left isomer of the complex chose minor groove optimally to recognize the A4 T5/TTG6 site next to the CPD and the right isomer chose major groove optimally to recognize the T6A7/G5T4 site bordering upon the other side of CPD. The DNA double helix was distorted seriously because of the existence of CPD. So the interaction was enantioselective and sitespecific and the left isomer was much more optimal compared with the right one. Detailed energy analysis indicated that the steric interaction in the process of the complex inserting tO base stacking determined the recognition results and the electrostatic interaction made an effect in some extent. The shape of two T bases forming CPD changed from mouth shape to approximate parallel shape after the complex intercalating DNA. That was the initial conformational repair.