与酗酒毒害性相关的细胞色素CYP2E1蛋白酶催化反应机理及动力学的理论研究

酗酒引起的慢性乙醇性肝损伤及并发症的防治是健康卫生领域关注的热点问题，而与乙醇中毒性肝损伤发病密切相关的细胞色P4502E蛋白酶（CYP2E1）在乙醇诱导下的结构-功能关系的研究仍存在很多争议及空白。本项目拟采用分子动力学模拟、量子力学与分子力学相结合的（QM/MM）方法，对乙醇诱导下CYP2E1反应体系中结构和机理的特征进行系统深入的理论研究。具体课题包含：（1）CYP2E1构象随乙醇浓度变化而改变的规律；（2）较高乙醇浓度下，CYP2E1代谢能力随乙醇浓度增加而增强的反应机理研究；（3）较高乙醇浓度下，催化系统进行支路解偶联（uncoupling）反应，生成大量活性氧物质ROS，引起肝损伤的氧化应激机制；（4）乙醇作为诱导物在CYP2E1代谢信号分子花生四烯酸过程中的作用机制。上述研究课题将填补相关机理研究空白，对现存争议的根源给出可靠的理论解释，从而为相关疾病防治提供积极的理论依据。

Alcoholic liver disease (ALD) and other alcoholism-related diseases (such as diabetes and psoriasis) are interesting hotspots in the hygiene and wealth field. There are controversy and vacancy on the acknowledgement of the relationship between structure and function of cytochrome P450 2E1 (CYP2E1 in short), regarded as the target of alcoholism-related diseases. In our projects, a systematic investigation on the geometric and mechanistic features of this CYP2E1 reaction system, by means of molecular dynamics dynamics, combined quantum mechanism and molecular mechanism (QM/MM) method. The research will focus on following interesting sub-projects: (a) the relationship between global conformational change of CYP2E1 and the ethanol concentration, (b) mechanistic study of the origin caused the special metabolic feature of CYP2E1-catalyzed ethanol oxidation, (c) generation of reactive oxygen species (ROS) involved in ethanol-induced uncoupling reactions, (d) and the inducer role of ethanol in arachidonic acid metabolism by CYP2E1. Our research will not only enrich the basic mechanistic research in P450 enzymes field, but also play a positive role in alcoholism-related new drug design and clinic therapy by providing clear biochemical insights into alcoholism-related diseases.