人与鼠阿尔茨海默氏症Aβ34507;白错误折叠机理的比较研究

项目名称： 人与鼠阿尔茨海默氏症Aβ34507;白错误折叠机理的比较研究

项目编号： No.30800184

项目类型： 青年科学基金项目

立项/批准年度： 2009

项目学科： 生物科学

项目作者： 申亮

作者单位： 山东理工大学

项目金额： 20万元

中文摘要： 本项目综合分子动力学模拟、量化计算、生物信息学等理论手段对人与鼠Aβ30340;动力学稳定性、金属离子络合特性等进行全面比较分析,取得主要成果包括：1.通过分子动力学模拟研究发现人和鼠Aβ30340;整体稳定性相差不大，且三个位点突变Arg5Gly、Tyr10Phe和His13Arg对Aβ25972;体稳定性的影响较小，因此鼠Aβ19981;易错误折叠的原因不能归为鼠Aβ27604;人Aβ20855;有更高的稳定性。2.采用量化计算方法研究了人与鼠Aβ19982;Cu(II) 的络合，得到了其最可能的络合模式，并进而阐释了人与鼠Aβ19982;Cu(II) 络合能力的差异。3.通过动力学模拟发现Cu(II)络合均一定程度上增强了人与鼠Aβ30340;稳定性，但其对人Aβ30340;影响更为显著,并分析了作用机理。4.动力学模拟研究表明人Aβ20013;1、7、23位Asp由L-型消旋为D-型均可降低Aβ-42)的稳定性，其中23位影响最为明显。5. 运用生物信息方法系统分析与AD发病有关的三个基因(APP、PSEN1和PSEN2)中的200多个突变，发现大部分突变具有较强的方向性，为研究AD的发病机理提供重要线索。6. 对AD的一药多靶治疗策略进行了探索，讨论了部分天然产物的作用机理。

中文关键词： 阿尔茨海默氏症；β#28096;粉样蛋白；错误折叠；分子动力学模拟；量子化学计算

英文摘要： Employing molecular dynamics simualtion, quantum chemical calculation and bioinformatics, this project investigated the differences in thermodynamic stability, copper ion chelating characters between human and murine amyloid　βeptide (Aβ The main findings are as follows: 1) Through molecular dynamics simulations, it was found that human and murine Aβxhibit comparable thermodynamic property. The simulations on the three single-point mutants also indicated that R5G, Y10F and H13R mutations affect little on the stability of the peptide. This implies that the non-occurrence of murine Aβggregation may not arise from the dynamic characters of the peptide. 2) Based on quantum chemical calculation, we determined the most stable chelating modes of human and murine Aβith Cu(II) and evaluated their binding affinities, which provides the molecular basis underlying the experimental differences in Cu(II)-binding potentials of the two peptides. 3) The effect of Cu(II)-chelation on the stbility of human and murine Aβas explored through molecular dynamics simulations and it was found that Cu(II)-chelation can enhance the stability of both human and murine Aβwhile the impact on human Aβs more significant than the murine counterpart. 4) Impact of aspartate racemization on the conformational stability of Aβ-42) was investigated by means of MD simulations and the results indicate that D-Asp1,7,23 substitutions decreased the conformational stability and accelerated the unfolding process of Aβ-42). Among the three positions, D-Asp23 substitution exhibited more significant impact than D-Asp1 and D-Asp7 substitutions. 5) Bioinformatic analysis on about 200 mutations in three AD-related genes (APP, PSEN1 and PSEN2) found that these mutations possess strong directional selection, i.e., enhancing hydrophobicity or decreasing negative and increasing positive charge, which provides important clues to understand the pathogenesis of AD. 6) We explored the "One-Compound-Multiple-Targets" strategy and investigated the pharmacology of selected natural products to combat AD.

英文关键词： Alzheimer's disease; Amyloid　βeptide; misfolding; molecular dynamics simualtion; quantum chemical calculation