Gerben Stacey R, Lemkul Justin A, Brown Anne M, Bevan David R
a Department of Biochemistry , Virginia Tech , 111 Engel Hall, Blacksburg , VA , 24061 , USA .
J Biomol Struct Dyn. 2014;32(11):1817-32. doi: 10.1080/07391102.2013.838518. Epub 2013 Sep 13.
Macromolecular function arises from structure, and many diseases are associated with misfolding of proteins. Molecular simulation methods can augment experimental techniques to understand misfolding and aggregation pathways with atomistic resolution, but the reliability of these predictions is a function of the parameters used for the simulation. There are many biomolecular force fields available, but most are validated using stably folded structures. Here, we present the results of molecular dynamics simulations on the intrinsically disordered amyloid β-peptide (Aβ), whose misfolding and aggregation give rise to the symptoms of Alzheimer's disease. Because of the link between secondary structure changes and pathology, being able to accurately model the structure of Aβ would greatly improve our understanding of this disease, and it may facilitate application of modeling approaches to other protein misfolding disorders. To this end, we compared five popular atomistic force fields (AMBER03, CHARMM22 + CMAP, GROMOS96 53A6, GROMOS96 54A7, and OPLS-AA) to determine which could best model the structure of Aβ. By comparing secondary structure content, NMR shifts, and radius of gyration to available experimental data, we conclude that AMBER03 and CHARMM22 + CMAP over-stabilize helical structure within Aβ, with CHARMM22 + CMAP also producing elongated Aβ structures, in conflict with experimental findings. OPLS-AA, GROMOS96 53A6, and GROMOS96 54A7 produce very similar results in terms of helical and β-strand content, calculated NMR shifts, and radii of gyration that agree well with experimental data.
大分子功能源于其结构，许多疾病都与蛋白质错误折叠有关。分子模拟方法可以辅助实验技术，以原子分辨率理解错误折叠和聚集途径，但这些预测的可靠性取决于模拟所使用的参数。有许多生物分子力场可供使用，但大多数是通过稳定折叠结构进行验证的。在此，我们展示了对内在无序的淀粉样β肽（Aβ）进行分子动力学模拟的结果，其错误折叠和聚集会引发阿尔茨海默病的症状。由于二级结构变化与病理学之间的联系，能够准确模拟Aβ的结构将极大地增进我们对这种疾病的理解，并且可能有助于将建模方法应用于其他蛋白质错误折叠疾病。为此，我们比较了五种常用的原子力场（AMBER03、CHARMM22 + CMAP、GROMOS96 53A6、GROMOS96 54A7和OPLS - AA），以确定哪种力场能最好地模拟Aβ的结构。通过将二级结构含量、核磁共振化学位移和回转半径与现有实验数据进行比较，我们得出结论：AMBER03和CHARMM22 + CMAP过度稳定了Aβ内的螺旋结构，CHARMM22 + CMAP还产生了拉长的Aβ结构，这与实验结果相矛盾。OPLS - AA、GROMOS96 53A6和GROMOS96 54A7在螺旋和β链含量、计算得到的核磁共振化学位移以及回转半径方面产生了非常相似的结果，这些结果与实验数据吻合良好。
