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

doi:10.7503/cjcu20180434

Abstract

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

CLC Number:

O641

TrendMD:

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

Figures/Tables 7

References 30

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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