Molecular Interactions of Alzheimer's Aβ Protofilaments with Lipid Membranes
Molecular Interactions of Alzheimer's Aβ Protofilaments with Lipid Membranes
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DOI：
10.1016/j.jmb.2011.12.063
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发表时间：
2012-08-24
影响因子：
5.6
通讯作者：
Buchete, Nicolae-Viorel
中科院分区：
文献类型：
--
作者：
Tofoleanu, Florentina;Buchete, Nicolae-Viorel
淀粉样蛋白原纤维和肽寡聚体在阿尔茨海默病、2型糖尿病、帕金森病、亨廷顿病和朊病毒相关疾病的病理学中起中心作用。在这里，我们调查的预成型淀粉样蛋白β（A β）分子原丝和脂质双层膜之间的分子相互作用，在明确的水分子的存在下，使用计算模型和全原子分子动力学。这些相互作用在A β原纤维和相邻细胞膜的稳定性和功能中起重要作用。利用原丝的方向性和相关性，我们建立了覆盖几个相对原丝膜取向的模型。我们的分子动力学模拟揭示了不同的结构元素的相对贡献的动态和稳定性的A β原丝段附近的膜，和原纤维膜相互作用的机制的第一步。在这个过程中，我们观察到一个显着的改变侧链接触模式的原丝，虽然一小部分的特征β-折叠内容被保留。作为一个主要的驱动力，我们确定了A β带电侧链，包括E22，D23和K28，和脂质头基之间的静电相互作用。与来自脂质头基的原子的氢键结合在一起，这些相互作用可以促进疏水性C-末端氨基酸通过脂质头基区域的渗透，这最终可以导致初始原纤维结构的进一步损失和局部膜变薄效应。我们的结果可能会指导新的实验，这些实验可以测试水形成的淀粉样蛋白原纤维的结构特征在多大程度上通过膜介导的相互作用被保留、丢失或重塑。(C)2012爱思唯尔有限公司保留所有权利。
Amyloid fibrils and peptide oligomers play central roles in the pathology of Alzheimer's disease, type 2 diabetes, Parkinson's disease, Huntington's disease, and prion-related disease. Here, we investigate the molecular interactions between preformed amyloid beta (A beta) molecular protofilaments and lipid bilayer membranes, in the presence of explicit water molecules, using computational models and all-atom molecular dynamics. These interactions play an important role in the stability and function of both A beta fibrils and the adjacent cellular membrane. Taking advantage of the symmetry-related and directional properties of the protofilaments, we build models that cover several relative protofilament membrane orientations. Our molecular dynamics simulations reveal the relative contributions of different structural elements to the dynamics and stability of A beta protofilament segments near membranes, and the first steps in the mechanism of fibril membrane interactions. During this process, we observe a significant alteration of the side-chain contact pattern in protofilaments, although a fraction of the characteristic beta-sheet content is preserved. As a major driving force, we identify the electrostatic interactions between A beta charged side chains, including E22, D23, and K28, and lipid headgroups. Together with hydrogen bonding with atoms from lipid headgroups, these interactions can facilitate the penetration of hydrophobic C-terminal amino acids through the lipid headgroup region, which can finally lead both to further loss of the initial fibril structure and to local membrane-thinning effects. Our results may guide new experiments that could test the extent to which the structural features of water-formed amyloid fibrils are preserved, lost, or reshaped by membrane-mediated interactions. (C) 2012 Elsevier Ltd. All rights reserved.