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In silico studies of solvated F19W amyloid beta (11-40) trimer

机译：在溶剂化F19W淀粉样蛋白β（11-40）三聚体的硅研究中

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摘要

Alzheimer's disease (AD) is associated with the oligomerization and/or fibrillation of amyloid beta (A beta) peptides, which cause damage to brain cells. A beta oligomers and fibrils contain hydrophobic cores formed with parallel beta sheets. Mutations of F19, a residue in the hydrophobic core of A beta peptides, slow down their aggregation process but do not alter the overall structure of the resulting fibrils. However, the effects of F19 mutations on the toxic A beta oligomers have not been elucidated. We studied the F19W mutant of the 11-40 truncated A beta trimer (F19W 3A beta(11-40)) using replica exchange molecular dynamics (REMD) simulations. While most structural terms do not change significantly, critical polar contacts decrease by 20%, and notably, RMSD almost doubles upon F19W mutation. Six minima were found in the free energy surface of F19W 3A beta(11-40), which have lower energy barriers (by similar to 1 kJ mol(-1)) and significantly lower total population (similar to 20%) compared to those of the three minima found for 3A beta(11-40) (similar to 60%). The binding free energy between constituting chains of the mutant trimer increases by similar to 28 kcal mol(-1) but fluctuates significantly (similar to 27.1 kcal mol(-1)). Our results indicate that while the hydrophobic core of amyloid beta peptide is capable of adapting to structural changes, F19W mutation results in a significantly more flexible trimer. The more flexible F19W mutant oligomers would require more time to self-assemble into fibrils. Our results contribute to a better understanding of the behavior of Ab peptides and their oligomerization/aggregation process, which is necessary to understand AD pathogenesis.
机译：阿尔茨海默病的疾病（AD）与淀粉样蛋白β（β）肽的寡聚和/或颤动有关，这导致脑细胞损伤。 β低聚物和原纤维含有由平行β板形成的疏水性芯。 F19的突变，β肽的疏水核中的残留物，减慢其聚集过程，但不改变所得原纤维的整体结构。然而，F19突变对毒性β低聚物的影响尚未得到阐明。我们研究了使用副本交换分子动力学（REMD）模拟的11-40截短的β三聚体（F19W3Aβ（11-40））的F19W突变体。虽然大多数结构术语不会显着变化，但临界极性接触减少了20％，特别是RMSD在F19W突变时几乎翻倍。在F19W3Aβ（11-40）的自由能表面中发现六项最小值，其具有较低的能量屏障（通过类似于1kJ摩尔（-1）），与那些相比，与1kJ摩尔（-1））显着降低总群体（类似于20％）对于3Aβ（11-40）发现的三个最小值（类似于60％）。构成突变分子分子链之间的无结合能量通过与28kcal摩尔（-1）相似而增加，但显着波动（类似于27.1kcal摩尔（-1））。我们的结果表明，虽然淀粉样蛋白β肽的疏水核心能够适应结构变化，但F19W突变导致了更具柔性的三聚体。更灵活的F19W突变体低聚物将需要更多的时间来自组装成原纤维。我们的结果有助于更好地了解AB肽及其低聚/聚集过程的行为，这对于了解AD发病机制是必要的。

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  • 来源
    《RSC Advances》 |2017年第67期|共8页
  • 作者

    Son Tung Ngo; Xuan-Cuong Luu; Minh Tung Nguyen; Le Chinh N.; Vu Van V.;

  • 作者单位

    Ton Duc Thang Univ Computat Chem Res Grp Ho Chi Minh City Vietnam;

    Nguyen Tat Thanh Univ NTT Hitech Inst Ho Chi Minh City Vietnam;

    Binh Duong Univ Thu Dau Mot City Binh Duong Prov Vietnam;

    Nguyen Tat Thanh Univ NTT Hitech Inst Ho Chi Minh City Vietnam;

    Nguyen Tat Thanh Univ NTT Hitech Inst Ho Chi Minh City Vietnam;

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  • 正文语种 eng
  • 中图分类 化学;
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