Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.
Role of water in mediating the assembly of Alzheimer amyloid-beta Abeta16-22 protofilaments.
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DOI：
10.1021/ja8017303
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发表时间：
2008-08-20
影响因子：
15
通讯作者：
Shea, Joan-Emma
中科院分区：
文献类型：
--
作者：
Krone, Mary Griffin;Hua, Lan;Soto, Patricia;Zhou, Ruhong;Berne, B. J.;Shea, Joan-Emma
用全原子分子动力学模拟研究了水在促进原丝(淀粉样蛋白纤维的基本构件)形成中的作用。我们的模型原丝由两个平行的β-Sheet阿尔茨海默病淀粉样蛋白-β16-22肽(Ac-K16-L17-V18-F19-F20-A21-E22-NH2)组成。每张纸都有一个不同的疏水和亲水表面，并一起自组装成一个稳定的原丝，其核心由纯疏水残基(L17，F19，A21)组成，两个带电残基(K16，E22)指向溶剂。我们的模拟揭示了水介导的组装和由形成原丝内部的特定残基之间有利的能量相互作用驱动的组装之间的微妙相互作用。在一些但不是所有的分子动力学轨迹中，观察到了去湿转变，其中水排出在疏水崩溃之前。在没有观察到去湿的轨迹中，水的排出和疏水崩溃同时发生，原丝组装由多肽的疏水侧链(特别是F-F残基之间)之间的直接相互作用驱动。对于相同的轨迹，模拟温度的小幅升高(约20K)或多肽-水范德华引力的适度降低(约10%)就足以诱导去湿转变，这表明模拟中脱湿转变的存在可能对力场参数化的细节很敏感。
The role of water in promoting the formation of protofilaments (the basic building blocks of amyloid fibrils) is investigated using fully atomic molecular dynamics simulations. Our model protofilament consists of two parallel β-sheets of Alzheimer Amyloid-β 16–22 peptides (Ac-K16-L17-V18-F19-F20-A21-E22-NH2). Each sheet presents a distinct hydrophobic and hydrophilic face and together self-assemble to a stable protofilament with a core consisting of purely hydrophobic residues (L17,F19,A21), with the two charged residues (K16, E22) pointing to the solvent. Our simulations reveal a subtle interplay between a water mediated assembly and one driven by favorable energetic interactions between specific residues forming the interior of the protofilament. A dewetting transition, in which water expulsion precedes hydrophobic collapse, is observed for some, but not all molecular dynamics trajectories. In the trajectories in which no dewetting is observed, water expulsion and hydrophobic collapse occur simultaneously, with protofilament assembly driven by direct interactions between the hydrophobic side chains of the peptides (particularly between F–F residues). For those same trajectories, a small increase in the temperature of the simulation (on the order of 20 K) or a modest reduction in the peptide–water van der Waals attraction (on the order of 10%) is sufficient to induce a dewetting transition, suggesting that the existence of a dewetting transition in simulation might be sensitive to the details of the force field parametrization.
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影响因子：
13.8
作者：
Dobson, CM
通讯作者：
Dobson, CM
影响因子：
4.4
作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG
影响因子：
64.8
作者：
Cheng, YK;Rossky, PJ
通讯作者：
Rossky, PJ
DOI：
10.1073/pnas.1934837100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Huang, X;Margulis, CJ;Berne, BJ
通讯作者：
Berne, BJ
影响因子：
15
作者：
Ashbaugh, HS;Paulaitis, ME
通讯作者：
Paulaitis, ME