Side chain interactions can impede amyloid fibril growth: replica exchange simulations of Abeta peptide mutant.
Side chain interactions can impede amyloid fibril growth: replica exchange simulations of Abeta peptide mutant.
复制标题
侧链相互作用可以阻碍淀粉样原纤维的生长：Abeta 肽突变体的复制品交换模拟。
DOI：
10.1021/jp904070w
复制
发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Klimov,DmitriK
中科院分区：
文献类型：
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作者：
Takeda,Takako;Klimov,DmitriK
利用复制品交换分子动力学，我们研究了 Asp23Tyr 突变对 Aβ10−40 原纤维生长的影响。通过计算自由能景观、肽-原纤维相互作用的分布以及与野生型 Aβ10−40 肽的比较，揭示了这种突变的影响。 Asp23Tyr 突变对 Aβ 肽与原纤维的对接影响相对较小。然而，由于原纤维边缘上的肽形成的平行注册内β-折叠的深度稳定，它对锁定阶段有很大的影响。平行 β-折叠的稳定性增强是由于 Asp23 形成的侧链相互作用被删除，而侧链相互作用与原纤维样构象异构体不相容。因此，Asp23Tyr 突变预计会促进原纤维生长。我们认为，强的注册外侧链相互作用可能会减慢原纤维的组装，就像野生型 Aβ 肽那样。实验数据的分析为我们的计算机结论提供了支持。
Using replica exchange molecular dynamics, we study the effect of Asp23Tyr mutation on Aβ10−40fibril growth. The effect of this mutation is revealed through the computation of free energy landscapes, the distributions of peptide−fibril interactions, and by comparison with the wild-type Aβ10−40peptide. Asp23Tyr mutation has a relatively minor influence on the docking of Aβ peptides to the fibril. However, it has a strong impact on the locking stage due to profound stabilization of the parallel in-registry β-sheets formed by the peptides on the fibril edge. The enhanced stability of parallel β-sheets results from the deletion of side chain interactions formed by Asp23, which are incompatible with the fibril-like conformers. Consequently, Asp23Tyr mutation is expected to promote fibril growth. We argue that strong off-registry side chain interactions may slow down fibril assembly as it occurs for the wild-type Aβ peptide. The analysis of experimental data offers support to ourin silicoconclusions.