项目名称： 靶向Bcl-2新型拮抗剂通过非典型结合域诱导抗凋亡功能转变分子机制的理论研究

项目编号： No.21603013

项目类型： 青年科学基金项目

立项/批准年度： 2017

项目学科： 数理科学和化学

项目作者： 崔颖璐

作者单位： 中国科学院微生物研究所

项目金额： 19万元

中文摘要： Bcl-2抗凋亡蛋白通过干扰线粒体介导的细胞凋亡通路，诱导肿瘤发生。然而，新型拮抗剂经非典型结合域作用可诱导Bcl-2由抗凋亡因子转变为促凋亡因子，为癌症治疗提供新型策略，具有重大应用前景。本项目拟采用多种分子动力学与必要量子力学计算相结合的研究方法，重点开展新型拮抗剂诱导Bcl-2抗凋亡功能转变的分子机制研究。项目计算分析新型拮抗剂及类似物与Bcl-2非典型结合域“诱导-契合”的作用模式，揭示新型拮抗剂特异性结合的结构基础，阐明特异性结合对BH4结构域重新定位和BH3结构域暴露的调控过程，解析多结构域协同变构分子机制，并进一步诠释变构效应对HBS与Bid作用的调控机制及干扰Bcl-XL的具体结合模式和抑制机制。在此基础上，阐明新型拮抗剂诱导的Bcl-2抗凋亡蛋白功能转化机制，实现微观靶向结合与宏观功能转换的有机关联，为加深细胞凋亡通路研究和新型癌症治疗提供有力的理论支持和方法贮备。

中文关键词： 分子动力学模拟；分子对接；B细胞淋巴瘤/白血病-2；蛋白质-小分子相互作用；变构调节

英文摘要： Bcl-2 proteins control multiple pathways of programmed cell death. In cancer cells, overexpression of anti-apoptotic members can serve as a driving force for tumorigenesis. However, recent studies have revealed that the novel inhibitors could induce the abrogation of Bcl-2 anti-apoptotic function, converting it from a survival molecule to a cell death inducer, which may provide a strategy to improve cancer therapy. In the present project, the molecular dynamics simulations coupled with necessary quantum mechanics calculation is adopted to explore the conformational change induced by the binding of novel inhibitors with Bcl-2 and its effect on the functional conversion of Bcl-2. Specifically, the mode of interaction between the atypical binding site with inhibitors will be evaluated to reveal its structural basis and specific selectivity. Subsequently, the tunning process of BH4 domain repositioning and BH3 domain exposure caused by the occupancy of ABS by the inhibitors will be elucidated, and the BH3 domain exposure-mediated release of Bid protein and inhibitory effect of Bcl-XL will then be demonstrated. Finally, the influence of the above ABS interactions on the conversion of Bcl-2 from an anti-apoptotic molecule into a pro-apoptotic protein will be delineated, bridging the gap between the theory and the experimentally observed results of functional conversion. The exploration in the present project may provide theoretical foundation and methodology support to both apoptotic pathway study and improvements of cancer therapy.

英文关键词： molecular dynamics simulations;molecular docking;B cell lymphoma/leukemia-2;protein-ligand interactions;allosteric control