Mechanistic insight into E22Q-mutation-induced antiparallel-to-parallel β-sheet transition of Aβ16-22 fibrils: an all-atom simulation study
Mechanistic insight into E22Q-mutation-induced antiparallel-to-parallel β-sheet transition of Aβ16-22 fibrils: an all-atom simulation study
复制标题
E22Q突变诱导的Aβ（16-22）原纤维反平行到平行β折叠转变的机制洞察：全原子模拟研究
DOI：
10.1039/c9cp02561h
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发表时间：
2019-07-28
影响因子：
3.3
通讯作者：
Wei, Guanghong
中科院分区：
文献类型：
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作者：
Li, Xuhua;Lei, Jiangtao;Wei, Guanghong
阿尔茨海默病与淀粉样β (Aβ) 肽异常自组装成有毒低聚物和原纤维有关。最近的实验报道，含有 A beta 中央疏水核心 (CHC) 的 A beta(16-22) 形成反平行 β 片原纤维，而其 E22Q 突变体自组装成平行 β 片原纤维。然而，E22Q 突变诱导平行 β-折叠原纤维形成的分子机制尚不清楚。在此，我们进行了分子动力学 (MD) 模拟来研究 A beta(16-22) 和 A beta(16-22)E22Q 肽的二聚过程。观察到具有不同氢键排列的β-片层二聚体，并且它们表现出高度动态和相互转换的特性。 E22Q 突变体的组装过程中发生了反平行到平行 β-折叠的转变，但 A beta(16-22) 的组装过程中则没有。在这个构象转变过程中，分子间的Q22-Q22氢键首先形成并充当粘合剂，促进两条链形成平行取向，然后CHC区域残基之间的疏水相互作用巩固了这种排列并驱动主链氢键形成，从而导致平行β-折叠的形成。然而，平行β-折叠的数量少于A beta(16-22)E22Q二聚体的反平行β-折叠。为了探索平行β-折叠是否在较大尺寸的寡聚物中占主导地位，我们通过进行复制交换分子动力学（REMD）模拟研究了A beta（16-22）和A beta（16-22）E22Q八聚体的构象整体。 REMD 模拟显示，平行 β 链排列的数量随着有序 A beta(16-22)E22Q β 折叠寡聚物尺寸的增加而增加，这意味着完全平行 β 折叠的形成需要更大尺寸的寡聚物。我们的研究结果为实验观察到的 E22Q 突变诱导的平行 β-折叠原纤维的形成提供了机制解释。
Alzheimer's disease is associated with the abnormal self-assembly of amyloid-beta (A beta) peptide into toxic oligomers and fibrils. Recent experiments reported that A beta(16-22), containing the central hydrophobic core (CHC) of A beta, formed antiparallel beta-sheet fibrils, while its E22Q mutant self-assembled into parallel beta-sheet fibrils. However, the molecular mechanisms underlying E22Q-mutation-induced parallel beta-sheet fibril formation are not well understood. Herein, we performed molecular dynamics (MD) simulations to study the dimerization processes of A beta(16-22) and A beta(16-22)E22Q peptides. beta-Sheet dimers with diverse hydrogen bond arrangements were observed and they exhibited highly dynamic and interconverting properties. An antiparallel-to-parallel beta-sheet transition occurred in the assembly process of the E22Q mutant, but not in that of A beta(16-22). During this conformational transformation process, the inter-molecular Q22-Q22 hydrogen bonds were first formed and acted as a binder to facilitate the two chains forming a parallel orientation, then the hydrophobic interactions between residues in the CHC region consolidated this arrangement and drove the main-chain H-bond formation, hence resulting in parallel beta-sheet formation. However, parallel beta-sheets were less populated than antiparallel beta-sheets of A beta(16-22)E22Q dimers. In order to explore whether parallel beta-sheets became dominant in larger size oligomers, we investigated the conformational ensembles of A beta(16-22) and A beta(16-22)E22Q octamers by conducting replica exchange molecular dynamics (REMD) simulations. The REMD simulations revealed that the population of parallel beta-strand alignment increased with an increase of the size of ordered A beta(16-22)E22Q beta-sheet oligomers, implying that the formation of full parallel beta-sheets requires larger sized oligomers. Our findings provide a mechanistic explanation for the E22Q-mutation-induced formation of parallel beta-sheet fibrils observed experimentally.