Fibril elongation by Aβ(17-42): kinetic network analysis of hybrid-resolution molecular dynamics simulations.
Fibril elongation by Aβ(17-42): kinetic network analysis of hybrid-resolution molecular dynamics simulations.
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DOI：
10.1021/ja507002p
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发表时间：
2014-09-03
影响因子：
15
通讯作者：
Schulten K
中科院分区：
文献类型：
--
作者：
Han W;Schulten K
β-淀粉样蛋白原纤维形成的一个关键步骤是原纤维的伸长，在此过程中，淀粉样蛋白-β单体在与原纤维末端结合后经历结构向原纤维结构的转变。人们对结构转变的原子细节仍知之甚少。到目前为止，由于Aβ纤维伸长的时间尺度很长，对结构转变的计算表征仅限于较短的Aβ片段(5-10AA)。为了克服计算时间的限制，我们将混合分辨模型与伞形采样和副本交换分子动力学相结合，总共进行了∼1.3ms的Aβ17-42纤维伸长的分子动力学模拟。有偏模拟的动力学网络分析导致了一个动力学模型，该模型涵盖了对纤维形成至关重要的所有Aβ片段。该模型不仅再现了实验中测得的纤维伸长的关键性质，包括Aβ结合亲和力、Aβ结构转变的活化热以及Aτ结合及其结构转变之间的大时间间隔(τLock/τDOCK=10 3-10 4)，而且揭示了涉及以前未见过的结构转变的详细路径，即在疏水区L17-A21和G37-A42中形成纤维先于亲水区E22-A30中的纤维形成。此外，该模型确定Aβ单体的链-环-链(SLS)结构是重要的动力学中间体，长期以来一直被怀疑与纤维伸长有关。动力学模型进一步表明，暴露L17-A21的纤维末端纤维伸长速度比另一末端更快，从而解释了先前在实验中观察到的单向纤维生长。
A critical step of β-amyloid fibril formation is fibril elongation in which amyloid-β monomers undergo structural transitions to fibrillar structures upon their binding to fibril tips. The atomic detail of the structural transitions remains poorly understood. Computational characterization of the structural transitions is limited so far to short Aβ segments (5–10 aa) owing to the long time scale of Aβ fibril elongation. To overcome the computational time scale limit, we combined a hybrid-resolution model with umbrella sampling and replica exchange molecular dynamics and performed altogether ∼1.3 ms of molecular dynamics simulations of fibril elongation for Aβ17–42. Kinetic network analysis of biased simulations resulted in a kinetic model that encompasses all Aβ segments essential for fibril formation. The model not only reproduces key properties of fibril elongation measured in experiments, including Aβ binding affinity, activation enthalpy of Aβ structural transitions and a large time scale gap (τlock/τdock = 103–104) between Aβ binding and its structural transitions, but also reveals detailed pathways involving structural transitions not seen before, namely, fibril formation both in hydrophobic regions L17-A21 and G37-A42 preceding fibril formation in hydrophilic region E22-A30. Moreover, the model identifies as important kinetic intermediates strand–loop–strand (SLS) structures of Aβ monomers, long suspected to be related to fibril elongation. The kinetic model suggests further that fibril elongation arises faster at the fibril tip with exposed L17-A21, rather than at the other tip, explaining thereby unidirectional fibril growth observed previously in experiments.
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影响因子：
2.9
作者：
Esler, WP;Stimson, ER;Maggio, JE
通讯作者：
Maggio, JE
影响因子：
5.6
作者：
Ban, T;Hoshino, M;Goto, Y
通讯作者：
Goto, Y
影响因子：
5.5
作者：
Han, Wei;Wan, Cheuk-Kin;Wu, Yun-Dong
通讯作者：
Wu, Yun-Dong
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
2.8
作者：
Dovidchenko, N. V.;Galzitskaya, O. V.
通讯作者：
Galzitskaya, O. V.