Side-chain hydrophobicity and the stability of Aβ16-22 aggregates
Side-chain hydrophobicity and the stability of Aβ16-22 aggregates
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DOI：
10.1002/pro.2164
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发表时间：
2012-12-01
期刊：
影响因子：
8
通讯作者：
Hansmann, Ulrich H. E.
中科院分区：
文献类型：
--
作者：
Berhanu, Workalemahu M.;Hansmann, Ulrich H. E.
最近使用 Aβ 疏水性片段的诱变研究表明，芳香族 p 堆积相互作用对于原纤维的形成可能并不重要。我们使用显式溶剂全原子分子动力学，通过探测位置 19 和 20 的芳香族 Phe 残基的 Leu、Ile 和 Ala 突变对 A beta 片段 A beta 1622 的双层六角链的影响，测试了这一猜想。由于这些模拟依赖于所用力场的准确性，我们首先评估了小淀粉样蛋白聚集体对各种力场的动态和稳定性依赖性。这些初步研究使我们选择 AMBER99SB-ILDN 作为多个 100 ns 长分子动力学模拟的力场，以探测野生型和突变寡聚物的稳定性。单点和双点突变体证实，大小和疏水性是疏水核心区（A beta 1622）聚集和稳定性的关键。这表明作为设计 A β 聚集抑制剂的途径，可以用大小和疏水性相似的天然和非天然氨基酸取代疏水区域 (A β 1622) 中的残基 (特别是 Phe 19 和 20)。
Recent mutagenesis studies using the hydrophobic segment of A beta suggest that aromatic p-stacking interactions may not be critical for fibril formation. We have tested this conjecture by probing the effect of Leu, Ile, and Ala mutation of the aromatic Phe residues at positions 19 and 20, on the double-layer hexametric chains of A beta fragment A beta 1622 using explicit solvent all-atom molecular dynamics. As these simulations rely on the accuracy of the utilized force fields, we first evaluated the dynamic and stability dependence on various force fields of small amyloid aggregates. These initial investigations led us to choose AMBER99SB-ILDN as force field in multiple long molecular dynamics simulations of 100 ns that probe the stability of the wild-type and mutants oligomers. Single-point and double-point mutants confirm that size and hydrophobicity are key for the aggregation and stability of the hydrophobic core region (A beta 1622). This suggests as a venue for designing A beta aggregation inhibitors the substitution of residues (especially, Phe 19 and 20) in the hydrophobic region (A beta 1622) with natural and non-natural amino acids of similar size and hydrophobicity.