Institute of Physics, Polish Academy of Sciences, Warsaw, Poland.
J Phys Chem B. 2011 Jun 9;115(22):7433-46. doi: 10.1021/jp1116728. Epub 2011 May 12.
The effects of beta-sheet breaker peptides KLVFF and LPFFD on the oligomerization of amyloid peptides were studied by all-atom simulations. It was found that LPFFD interferes the aggregation of Aβ(16-22) peptides to a greater extent than does KLVFF. Using the molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) method, we found that the former binds more strongly to Aβ(16-22). Therefore, by simulations, we have clarified the relationship between aggregation rates and binding affinity: the stronger the ligand binding, the slower the oligomerization process. The binding affinity of pentapeptides to full-length peptide Aβ(1-40) and its mature fibrils has been considered using the Autodock and MM-PBSA methods. The hydrophobic interaction between ligands and receptors plays a more important role for association than does hydrogen bonding. The influence of beta-sheet breaker peptides on the secondary structures of monomer Aβ(1-40) was studied in detail, and it turns out that, in their presence, the total beta-sheet content can be enhanced. However, the aggregation can be slowed because the beta-content is reduced in fibril-prone regions. Both pentapeptides strongly bind to monomer Aβ(1-40), as well as to mature fibrils, but KLVFF displays a lower binding affinity than LPFFD. Our findings are in accord with earlier experiments that both of these peptides can serve as prominent inhibitors. In addition, we predict that LPFFD inhibits/degrades the fibrillogenesis of full-length amyloid peptides better than KLVFF. This is probably related to a difference in their total hydrophobicities in that the higher the hydrophobicity, the lower the inhibitory capacity. The GROMOS96 43a1 force field with explicit water and the force field proposed by Morris et al. (Morris et al. J. Comput. Chem. 1998, 19, 1639 ) were employed for all-atom molecular dynamics simulations and Autodock experiments, respectively.
采用全原子模拟研究了β-折叠破坏肽 KLVFF 和 LPFFD 对淀粉样肽寡聚化的影响。结果发现，LPFFD 比 KLVFF 更能干扰 Aβ（16-22）肽的聚集。使用分子力学-泊松-玻尔兹曼表面面积（MM-PBSA）方法，我们发现前者与 Aβ（16-22）结合得更牢固。因此，通过模拟，我们阐明了聚集速率与结合亲和力之间的关系：配体结合越强，寡聚化过程越慢。采用 Autodock 和 MM-PBSA 方法研究了五肽与全长肽 Aβ（1-40）及其成熟纤维的结合亲和力。配体与受体之间的疏水相互作用比对氢键的结合更重要。详细研究了β-折叠破坏肽对单体 Aβ（1-40）二级结构的影响，结果表明，在它们存在的情况下，总β-折叠含量可以增强。然而，由于在倾向于形成纤维的区域中β-含量降低，因此可以减缓聚集。这两种五肽都强烈地与单体 Aβ（1-40）以及成熟纤维结合，但 KLVFF 的结合亲和力低于 LPFFD。我们的研究结果与先前的实验结果一致，这两种肽都可以作为有效的抑制剂。此外，我们预测 LPFFD 比 KLVFF 更能抑制/降解全长淀粉样肽的纤维形成。这可能与它们总疏水性的差异有关，疏水性越高，抑制能力越低。采用 GROMOS96 43a1 力场和 Morris 等人提出的力场（Morris 等人，J. Comput. Chem. 1998，19，1639）分别进行全原子分子动力学模拟和 Autodock 实验。
