Replica exchange simulations of the thermodynamics of Abeta fibril growth.
Replica exchange simulations of the thermodynamics of Abeta fibril growth.
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DOI：
10.1016/j.bpj.2008.10.008
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发表时间：
2009-01
影响因子：
3.4
通讯作者：
Takako Takeda;D. Klimov
中科院分区：
文献类型：
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作者：
Takako Takeda;D. Klimov
利用复制交换分子动力学和全原子隐式溶剂模型研究了阿尔茨海默a β单体在预制淀粉样原纤维上沉积的热力学。与实验结果一致，确定了两个沉积阶段。对接阶段发生在一个很宽的温度范围内，从500 K时形成第一个肽-原纤维相互作用开始。当肽在380 K的温度下完全吸附在纤维边缘时，对接完成。对接转变似乎是连续的，并且在没有自由能势垒或中间体的情况下发生。在对接过程中，进入的a β单体在纤维边缘呈无序结构。锁定阶段发生在≈360 K的温度下，其特征是自由能的起伏。当进入的a β肽在纤维边缘形成平行的β片结构时，锁定发生。由于锁定的a - β肽形成的β片通常是不注册的，锁定相的结构与原纤维内部的结构不同。该研究还报告了两种不同的纤维边缘对传入的a β肽的结合亲和力是不同的。与结合在凸边的肽相比，结合在凹边的肽具有明显较低的自由能。并与现有实验数据进行了比较。
Replica exchange molecular dynamics and an all-atom implicit solvent model are used to probe the thermodynamics of deposition of Alzheimer's Aβmonomers on preformed amyloid fibrils. Consistent with the experiments, two deposition stages have been identified. The docking stage occurs over a wide temperature range, starting with the formation of the first peptide-fibril interactions at 500 K. Docking is completed when a peptide fully adsorbs on the fibril edge at the temperature of 380 K. The docking transition appears to be continuous, and occurs without free energy barriers or intermediates. During docking, incoming Aβmonomer adopts a disordered structure on the fibril edge. The locking stage occurs at the temperature of ≈360 K and is characterized by the rugged free energy landscape. Locking takes place when incoming Aβpeptide forms a parallelβ-sheet structure on the fibril edge. Because theβ-sheets formed by locked Aβpeptides are typically off-registry, the structure of the locked phase differs from the structure of the fibril interior. The study also reports that binding affinities of two distinct fibril edges with respect to incoming Aβpeptides are different. The peptides bound to the concave edge have significantly lower free energy compared to those bound on the convex edge. Comparison with the available experimental data is discussed.