Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide.
Probing the origins of increased activity of the E22Q "Dutch" mutant Alzheimer's beta-amyloid peptide.
复制标题
探究 E22Q“Dutch”突变型阿尔茨海默病 β-淀粉样肽活性增强的起源。
DOI：
10.1016/s0006-3495(01)75734-7
复制
发表时间：
2001
影响因子：
3.4
通讯作者：
Straub,JE
中科院分区：
文献类型：
--
作者：
Massi,F;Straub,JE
淀粉样多肽同系物Aβ(10-35)-NH2在水环境中以野生型(WT)和E22Q“荷兰”突变形式被模拟。对荷兰突变引起的沉积活性显著增加的原因进行了研究。使用多肽的平均结构、水合作用、构象波动和动力学的各种测量来执行和分析多个纳秒时间尺度的分子动力学轨迹。研究结果支持以下结论：1)E22Q突变体和WT肽均稳定在与Zhang等人的WT结构一致的“折叠卷曲”构象中。(2000)，J.Struct.Biol.130：130-141)；2)E22Q多肽在溶液中更灵活，支持早期关于其平衡结构波动大于WT多肽的说法；以及3)局部E22Q突变导致多肽的“疏水斑块”区域的第一溶剂化层发生变化，导致突变多肽的疏水溶剂化。模拟结果支持这样的观点，即荷兰突变导致的活性显著增加是由于解溶过程的加强，而去溶过程是多肽聚集的关键步骤。
The amyloid peptide congener Aβ(10–35)-NH2is simulated in an aqueous environment in both the wild type (WT) and E22Q "Dutch" mutant forms. The origin of the noted increase in deposition activity resulting from the Dutch mutation is investigated. Multiple nanosecond time scale molecular dynamics trajectories were performed and analyzed using a variety of measures of the peptide's average structure, hydration, conformational fluctuations, and dynamics. The results of the study support the conclusions that 1) the E22Q mutant and WT peptide are both stable in "collapsed coil" conformations consistent with the WT structure of Zhang et al. (2000,J. Struct. Biol.130:130–141); 2) the E22Q peptide is more flexible in solution, supporting early claims that its equilibrium structural fluctuations are larger than those of the WT peptide; and 3) the local E22Q mutation leads to a change in the first solvation layer in the region of the peptide's "hydrophobic patch," resulting in a more hydrophobic solvation of the mutant peptide. The simulation results support the view that the noted increase in activity due to the Dutch mutation results from an enhancement of the desolvation process that is an essential step in the aggregation of the peptide.