Department of Pharmaceutical Sciences, School of Pharmacy , University of Pittsburgh , Pittsburgh , Pennsylvania 15261 , United States.
Laboratoire de Biochimie Théorique UPR 9080, CNRS , Université Denis Diderot, Sorbonne Paris Cité, IBPC , 13 Rue Pierre et Marie Curie , 75005 Paris , France.
J Chem Theory Comput. 2019 Feb 12;15(2):1440-1452. doi: 10.1021/acs.jctc.8b01107. Epub 2019 Jan 28.
We investigated the effects of 17 widely used atomistic molecular mechanics force fields (MMFFs) on the structures and kinetics of amyloid peptide assembly. To this end, we performed large-scale all-atom molecular dynamics simulations in explicit water on the dimer of the seven-residue fragment of the Alzheimer's amyloid-β peptide, Aβ16-22, for a total time of 0.34 ms. We compared the effects of these MMFFs by analyzing various global reaction coordinates, secondary structure contents, the fibril population, the in-register and out-of-register architectures, and the fibril formation time at 310 K. While the AMBER94, AMBER99, and AMBER12SB force fields do not predict any β-sheets, the seven force fields, AMBER96, GROMOS45a3, GROMOS53a5, GROMOS53a6, GROMOS43a1, GROMOS43a2, and GROMOS54a7, form β-sheets rapidly. In contrast, the following five force fields, AMBER99-ILDN, AMBER14SB, CHARMM22*, CHARMM36, and CHARMM36m, are the best candidates for studying amyloid peptide assembly, as they provide good balances in terms of structures and kinetics. We also investigated the assembly mechanisms of dimeric Aβ16-22 and found that the fibril formation rate is predominantly controlled by the total β-strand content.
我们研究了 17 种广泛使用的原子分子力学力场（MMFFs）对淀粉样肽组装结构和动力学的影响。为此，我们在明水环境中对阿尔茨海默病淀粉样β肽 Aβ16-22 的七残基片段二聚体进行了大规模的全原子分子动力学模拟，总时间为 0.34 毫秒。我们通过分析各种全局反应坐标、二级结构含量、原纤维种群、同规和非同规结构以及在 310 K 时的原纤维形成时间，比较了这些 MMFFs 的影响。虽然 AMBER94、AMBER99 和 AMBER12SB 力场不能预测任何β-折叠，但有 7 种力场，即 AMBER96、GROMOS45a3、GROMOS53a5、GROMOS53a6、GROMOS43a1、GROMOS43a2 和 GROMOS54a7，能够迅速形成β-折叠。相比之下，以下五种力场，即 AMBER99-ILDN、AMBER14SB、CHARMM22*、CHARMM36 和 CHARMM36m，是研究淀粉样肽组装的最佳候选者，因为它们在结构和动力学方面提供了良好的平衡。我们还研究了二聚体 Aβ16-22 的组装机制，发现原纤维形成速率主要受总β-链含量控制。
