Charge states rather than propensity for beta-structure determine enhanced fibrillogenesis in wild-type Alzheimer's beta-amyloid peptide compared to E22Q Dutch mutant.
Charge states rather than propensity for beta-structure determine enhanced fibrillogenesis in wild-type Alzheimer's beta-amyloid peptide compared to E22Q Dutch mutant.
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与 E22Q Dutch 突变体相比，野生型阿尔茨海默病 β-淀粉样蛋白肽中纤维生成的增强是由电荷状态而非 β 结构倾向决定的。
DOI：
10.1110/ps.3150102
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Straub,JohnE
中科院分区：
文献类型：
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作者：
Massi,Francesca;Klimov,D;Thirumalai,D;Straub,JohnE
阿尔茨海默氏症淀粉样β肽的活性是肽序列的敏感功能。已经观察到阿尔茨海默氏淀粉样蛋白β肽的E22 Q荷兰突变体相对于野生型肽的原纤维伸长速率增加。增加的活性归因于相对于WT肽，在溶液中单体E22 Q突变体肽中形成β结构的更大倾向。使用Aβ（10-35）肽的WT和Dutch突变体形式在水溶液中的4纳秒时间尺度模拟来检验该假设。模拟结果表明，在E22 Q突变肽中形成β-结构的倾向并不比在WT肽中更大。观察到WT和突变体肽两者的中心疏水簇区域中螺旋结构的“闪烁”的显著量度。模拟结果反驳了荷兰突变导致在水溶液中单体肽中形成β结构的概率更高的假设。我们提出溶剂化WT肽相对于E22 Q突变体肽的更大稳定性导致前者的原纤维伸长速率降低。稳定性差异是由于两种肽的不同电荷状态。另一个建议导致预测WT和突变体E22 Q的原纤维伸长速率在酸性条件下应该是相似的。
The activity of the Alzheimer's amyloid β‐peptide is a sensitive function of the peptide's sequence. Increased fibril elongation rate of the E22Q Dutch mutant of the Alzheimer's amyloid β‐peptide relative to that of the wild‐type peptide has been observed. The increased activity has been attributed to a larger propensity for the formation of β structure in the monomeric E22Q mutant peptide in solution relative to the WT peptide. That hypothesis is tested using four nanosecond timescale simulations of the WT and Dutch mutant forms of the Aβ(10–35)‐peptide in aqueous solution. The simulation results indicate that the propensity for formation of β‐structure is no greater in the E22Q mutant peptide than in the WT peptide. A significant measure of “flickering” of helical structure in the central hydrophobic cluster region of both the WT and mutant peptides is observed. The simulation results argue against the hypothesis that the Dutch mutation leads to a higher probability of formation of β‐structure in the monomeric peptide in aqueous solution. We propose that the greater stability of the solvated WT peptide relative to the E22Q mutant peptide leads to decreased fibril elongation rate in the former. Stability difference is due to the differing charge state of the two peptides. The other proposal leads to the prediction that the fibril elongation rates for the WT and the mutant E22Q should be similar under acid conditions.