3种改性小分子对不同Aβ42纤维结构稳定性的影响机制研究

Effects of Three New Modified Molecules on the Structural Stability of Different Aβ42 Fibers

淀粉样蛋白(Aβ)的错误聚集是阿尔茨海默症(AD)的关键病理诱发因素,主要通过Aβ的自聚集和金属离子诱导聚集两种方式实现.实验结果表明,食用樱桃红(ER)、丹参酮(TS)、氯碘喹啉(CQ)在不同程度上都能起到抑制淀粉样蛋白聚集的作用,但其作用机制大不相同.将ER,TS和CQ分子结构进行两两重组,获得3种新的活性分子,使其兼具金属螯合、旋转键及N-末端区域(NR)结合的复合优势.结果发现,改性分子对不同Aβ42聚集体的作用各异.有的改性小分子对纤维起到解聚集的效果,而有的则增加纤维的稳定性;有的小分子对一种纤维结构起到解聚集的效果,而对另一种则起到稳定的作用.并发现尽管小分子的负电基团与同带负电的Aβ纤维有很强的排斥作用,但其对某些构型依然有解聚集的效果.

The misfolding and aggregation of amyloid-β(Aβ)peptides,which result from Aβself-aggregation and aggregation induced by metal ion,are the key factors in the pathogenesis of Alzheimer’s diseases(AD).It has experimentally been verified that erythrosine B(ER),Tanshinone(TS)and clioquinol(CQ)can inhibit the aggregation of amyloid peptides in different degree.However,the exact interaction mechanisms of these molecules are different.Through breaking and reorganizing the structure of these drug molecules in combination with their qualities,we designed three new modified molecules for AD treatment in silico and expected that they could possess the composite advantages of metal chelation,rotating bonds and NR binding preference.The results showed that modified molecules have different effects on distinct conformer of Aβ42 fibers.Some of them can disassemble the aggregated fibers,while others increase the fibrous stability.In particular,some small molecules disassemble amyloid fiber in a specific mode but play an inverse stability role in another.It was found for the first time that although some small negative-charged molecules have strong repulsive effect on the like charged fiber,their interaction still has an ability to disassemble certain fibrous conformers.This discovery provides a new pathway to disassemble or stabilize amyloid fiber and even to design new drugs by modification of modified small molecules.