Triguero Luciano, Singh Rajiv, Prabhakar Rajeev
Department of Chemistry, University of Miami, 1301 Memorial Drive, Coral Gables, FL 33146, USA.
J Phys Chem B. 2008 Jun 12;112(23):7123-31. doi: 10.1021/jp801168v. Epub 2008 May 14.
In this study, all-atom 50 ns molecular dynamics simulations are performed on the full-length amyloid beta (Abeta) monomers (WT-Abeta(1-40) and WT-Abeta(1-42)) and their oxidized forms (Met35(O)-Abeta(1-40) and Met35(O)-Abeta(1-42)) in aqueous solution. The effects of the oxidation state of Met35 and the presence of dipeptide (Ile41-Ala42) on the secondary structures of the three distinct regions (the central hydrophobic core region 17-21 (LVFFA), the loop 23-28 (DVGSNK), and the second hydrophobic domain 29-35 (GAIIGLM)) of all monomers have been analyzed in detail, and results are compared with the available experimental information. Our simulations indicate that the WT-Abeta(1-40) monomer adopts an overall beta-hairpin-like structure, which is promoted by the turn region (24-27). This turn region is stabilized through salt-bridge formation between the Asp23 and Lys28 residues. In contrast, the overall structure of the oxidized (Met35(O)-Abeta(1-40)) monomer can be divided into three well-defined bend regions separated by coil segments. These structural differences may be critical for the measured decrease in the rate of aggregation of Met35(O)-Abeta(1-40) peptide. In the WT-Abeta(1-42) monomer, in comparison to the WT-Abeta(1-40), the Asp23-Lys28 salt bridge is absent, and consequently, the turn in the middle (24-27) region has a smaller curvature. The observed difference in the aggregation rates of these two peptides may be related to the opening of the turn (24-27) stabilized by the Asp23-Lys28 salt bridge. For WT-Abeta(1-42), in the absence of this salt bridge, the unfolding and aggregation events may be more favorable than for WT-Abeta(1-40).
在本研究中，对全长淀粉样β（Aβ）单体（野生型Aβ(1 - 40)和野生型Aβ(1 - 42)）及其氧化形式（Met35(O)-Aβ(1 - 40)和Met35(O)-Aβ(1 - 42)）在水溶液中进行了全原子50纳秒分子动力学模拟。详细分析了Met35的氧化状态和二肽（Ile41 - Ala42）的存在对所有单体三个不同区域（中央疏水核心区域17 - 21（LVFFA）、环23 - 28（DVGSNK）和第二个疏水结构域29 - 35（GAIIGLM））二级结构的影响，并将结果与现有的实验信息进行了比较。我们的模拟表明，野生型Aβ(1 - 40)单体采用整体β - 发夹样结构，这是由转折区域（24 - 27）促进的。该转折区域通过Asp23和Lys28残基之间形成盐桥而稳定。相比之下，氧化型（Met35(O)-Aβ(1 - 40)）单体的整体结构可分为由螺旋片段分隔的三个明确的弯曲区域。这些结构差异可能对测量的Met35(O)-Aβ(1 - 40)肽聚集速率降低至关重要。在野生型Aβ(1 - 42)单体中，与野生型Aβ(1 - 40)相比，不存在Asp23 - Lys28盐桥，因此，中间（24 - 27）区域的转折曲率较小。观察到的这两种肽聚集速率的差异可能与由Asp23 - Lys28盐桥稳定的转折（24 - 27）的打开有关。对于野生型Aβ(1 - 42)，在没有这种盐桥的情况下，展开和聚集事件可能比野生型Aβ(1 - 40)更有利。
