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

doi:10.7503/cjcu20180434

摘要/Abstract

摘要：

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.

关键词: 淀粉样蛋白纤维, 改性小分子, 稳定性, 解聚集, 结合能

Abstract:

The misfolding and aggregation of amyloid-β(Aβ) peptides, which result from Aβ self-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.

Key words: Amyloid-β42 fiber;, Small modified molecule, Stabilization, Disassembly, Binding energy

中图分类号:

O641

TrendMD:

李金星, 邢晓凤, 齐中囡, 艾洪奇. 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. 高等学校化学学报, 2018, 39(10): 2230.

LI Jinxing,XING Xiaofeng,QI Zhongnan,AI Hongqi. Effects of Three New Modified Molecules on the Structural Stability of Different Aβ42 Fibers^†. Chem. J. Chinese Universities, 2018, 39(10): 2230.

图/表 7

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Name	Component	Name	Component
2BEG	Aβ42 pentamer	2ME2	2MXU+12×E2C
2BE1	2BEG+10×E1C	2MTS	2MXU+12×TSC
2BE2	2BEG+10×E2C	5KK3	Aβ42 di-hexamer
2BTS	2BEG+10×TSC	5KE1	5KK3+24×E1C
2MXU	Aβ42 hexamer	5KE2	5KK3+24×E2C
2ME1	2MXU+12×E1C	5KTS	5KK3+24×TSC

Name	Component	Name	Component
2BEG	Aβ42 pentamer	2ME2	2MXU+12×E2C
2BE1	2BEG+10×E1C	2MTS	2MXU+12×TSC
2BE2	2BEG+10×E2C	5KK3	Aβ42 di-hexamer
2BTS	2BEG+10×TSC	5KE1	5KK3+24×E1C
2MXU	Aβ42 hexamer	5KE2	5KK3+24×E2C
2ME1	2MXU+12×E1C	5KTS	5KK3+24×TSC

Complex	Probability(%)				Complex	Probability(%)
Complex	Coil	β-Sheet	Bend	Turn	Complex	Coil	β-Sheet	Bend	Turn
2BEG	29	54	14	1	2ME2	15	74	7	1
2BE1	30	52	15	1	2MTS	18	71	7	2
2BE2	30	51	12	2	5KK3	30	55	12	1
2BTS	26	54	13	3	5KE1	28	62	8	0
2MXU	19	72	6	1	5KE2	29	56	12	1
2ME1	14	78	6	1	5KTS	30	57	10	1

Complex	Probability(%)				Complex	Probability(%)
Complex	Coil	β-Sheet	Bend	Turn	Complex	Coil	β-Sheet	Bend	Turn
2BEG	29	54	14	1	2ME2	15	74	7	1
2BE1	30	52	15	1	2MTS	18	71	7	2
2BE2	30	51	12	2	5KK3	30	55	12	1
2BTS	26	54	13	3	5KE1	28	62	8	0
2MXU	19	72	6	1	5KE2	29	56	12	1
2ME1	14	78	6	1	5KTS	30	57	10	1

Complex	ΔE_vdw/(kJ·mol^-1)	ΔE_eler/(kJ·mol^-1)	ΔE_GB/(kJ·mol^-1)	ΔE_np/(kJ·mol^-1)	ΔE_b/(kJ·mol^-1)
2BE1	-129.5	275.3	218.3	-16.1	348.0
2BE2	-297.3	388.8	167.5	-27.8	231.2
2BTS	-260.0	-19.5	117.9	-25.5	-187.1
2ME1	-128.5	302.9	263.3	-15.4	422.2
2ME2	-197.5	362.7	173.8	-18.4	320.7
2MTS	-232.4	-53.2	126.3	-20.5	-179.8
5KE1	-123.4	493.9	156.1	-15.4	511.2
5KE2	-241.7	677.1	119.9	-22.2	533.1
5KTS	-225.6	-32.4	134.8	-21.4	-144.6