淀粉样β二聚体形成的分子动力学模拟
Molecular Dynamics Simulation of Amyloid Beta Dimer Formation
摘要：
最近对淀粉样蛋白-β（Abeta）肽的实验表明，毒性寡聚体的形成可能是阿尔茨海默病发病的重要原因。Abeta寡聚体的毒性取决于它们的结构，这是由组装动力学。由于目前实验技术的局限性，缺少在原子水平上对低聚物结构的详细了解。我们引入了一种分子动力学方法来研究Abeta二聚体的形成：（1）我们使用离散的分子动力学模拟的粗粒度模型来识别各种二聚体构象，（2）我们采用全原子分子力学模拟来估计所有二聚体构象的热力学稳定性。我们的粗粒度Abeta肽模型的模拟预测十个不同的平面β链二聚体构象。然后，我们估计的自由能的所有二聚体构象在全原子分子力学模拟明确的水。我们比较了Abeta（1-42）和Abeta（1-40）二聚体的自由能。我们发现，（a）所有的二聚体构象具有更高的自由能相比，其相应的单体状态，和（b）之间的自由能差异的Abeta（1-42）和类似的Abeta（1-40）二聚体构象是不显着的。我们的研究结果表明，Abeta寡聚化并不伴随着形成稳定的平面β链Abeta二聚体。
英文摘要：
Recent experiments with amyloid-beta (Abeta) peptide suggest that formation of toxic oligomers may be an important contribution to the onset of Alzheimer's disease. The toxicity of Abeta oligomers depends on their structure, which is governed by assembly dynamics. Due to limitations of current experimental techniques, a detailed knowledge of oligomer structure at the atomic level is missing. We introduce a molecular dynamics approach to study Abeta dimer formation: (1) we use discrete molecular dynamics simulations of a coarse-grained model to identify a variety of dimer conformations, and (2) we employ all-atom molecular mechanics simulations to estimate the thermodynamic stability of all dimer conformations. Our simulations of a coarse-grained Abeta peptide model predicts ten different planar beta-strand dimer conformations. We then estimate the free energies of all dimer conformations in all-atom molecular mechanics simulations with explicit water. We compare the free energies of Abeta(1-42) and Abeta(1-40) dimers. We find that (a) all dimer conformations have higher free energies compared to their corresponding monomeric states, and (b) the free energy difference between the Abeta(1-42) and the analogous Abeta(1-40) dimer conformation is not significant. Our results suggest that Abeta oligomerization is not accompanied by the formation of stable planar beta-strand Abeta dimers.
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