Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
PLoS Comput Biol. 2010 Feb 5;6(2):e1000663. doi: 10.1371/journal.pcbi.1000663.
The relationship between Apolipoprotein E (ApoE) and the aggregation processes of the amyloid beta (A beta) peptide has been shown to be crucial for Alzheimer's disease (AD). The presence of the ApoE4 isoform is considered to be a contributing risk factor for AD. However, the detailed molecular properties of ApoE4 interacting with the A beta peptide are unknown, although various mechanisms have been proposed to explain the physiological and pathological role of this relationship. Here, computer simulations have been used to investigate the process of A beta interaction with the N-terminal domain of the human ApoE isoforms (ApoE2, ApoE3 and ApoE4). Molecular docking combined with molecular dynamics simulations have been undertaken to determine the A beta peptide binding sites and the relative stability of binding to each of the ApoE isoforms. Our results show that from the several ApoE isoforms investigated, only ApoE4 presents a misfolded intermediate when bound to A beta. Moreover, the initial alpha-helix used as the A beta peptide model structure also becomes unstructured due to the interaction with ApoE4. These structural changes appear to be related to a rearrangement of the salt bridge network in ApoE4, for which we propose a model. It seems plausible that ApoE4 in its partially unfolded state is incapable of performing the clearance of A beta, thereby promoting amyloid forming processes. Hence, the proposed model can be used to identify potential drug binding sites in the ApoE4-A beta complex, where the interaction between the two molecules can be inhibited.
载脂蛋白 E（ApoE）与淀粉样β（Aβ）肽的聚集过程之间的关系对于阿尔茨海默病（AD）至关重要。载脂蛋白 E4 同工型的存在被认为是 AD 的一个促成风险因素。然而，ApoE4 与 Aβ肽相互作用的详细分子特性尚不清楚，尽管已经提出了各种机制来解释这种关系的生理和病理作用。在这里，我们使用计算机模拟研究了 Aβ与人类 ApoE 同工型（ApoE2、ApoE3 和 ApoE4）的 N 端结构域相互作用的过程。进行了分子对接结合分子动力学模拟，以确定 Aβ肽的结合位点以及与每种 ApoE 同工型结合的相对稳定性。我们的结果表明，在所研究的几种 ApoE 同工型中，只有 ApoE4 在与 Aβ结合时呈现出错误折叠的中间体。此外，由于与 ApoE4 的相互作用，最初用作 Aβ肽模型结构的α螺旋也变得无结构。这些结构变化似乎与 ApoE4 中盐桥网络的重排有关，我们为此提出了一个模型。似乎合理的是，部分展开状态的 ApoE4 无法清除 Aβ，从而促进了淀粉样形成过程。因此，所提出的模型可用于鉴定 ApoE4-Aβ 复合物中的潜在药物结合位点，其中可以抑制两个分子之间的相互作用。
