The combined force field-sampling problem in simulations of disordered amyloid-β peptides
The combined force field-sampling problem in simulations of disordered amyloid-β peptides
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DOI：
10.1063/1.5078615
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发表时间：
2019-03-14
影响因子：
4.4
通讯作者：
Head-Gordon, Teresa
中科院分区：
文献类型：
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作者：
Lincoff, James;Sasmal, Sukanya;Head-Gordon, Teresa
如果力场足够精确，并且模拟充分采样了具有正确亚种群权重的内在无序蛋白的构象空间，则分子动力学模拟可以提供高分辨率的结构集成。在这里，我们通过测试标准力场和较新的固定电荷力场来研究联合力场采样问题，后者专门用于更好地描述展开状态和IDPs，并将它们与标准温度副本交换（TREx）协议和非平衡温度冷行走（TCW）采样算法进行比较。利用力场和采样组合来表征淀粉样β肽A β 42和A β 43的结构集合体，它们都应该是随机线圈，最近的实验核磁共振（NMR）和二维福斯特共振能量转移（FRET）实验表明。结果说明了采样算法的关键重要性：虽然使用TREx的标准力场与核磁共振j -耦合、核Overhauser效应和二维FRET数据的一致性较差，但使用TCW方法时，标准和优化的蛋白质-水力场组合与相同的实验数据的一致性很好，因为TCW采样方法与TREx采样方法产生的集成在质量上不同。我们还讨论了二维FRET数据在使用不同的力场和采样方案验证结构集成时的相对优点，在这项工作中研究了小IDPs，如A β 42和A β 43肽。
Molecular dynamics simulations of intrinsically disordered proteins (IDPs) can provide high resolution structural ensembles if the force field is accurate enough and if the simulation sufficiently samples the conformational space of the IDP with the correct weighting of sub-populations. Here, we investigate the combined force field-sampling problem by testing a standard force field as well as newer fixed charge force fields, the latter specifically motivated for better description of unfolded states and IDPs, and comparing them with a standard temperature replica exchange (TREx) protocol and a non-equilibrium Temperature Cool Walking (TCW) sampling algorithm. The force field and sampling combinations are used to characterize the structural ensembles of the amyloid-beta peptides A beta 42 and A beta 43, which both should be random coils as shown recently by experimental nuclear magnetic resonance (NMR) and 2D Forster resonance energy transfer (FRET) experiments. The results illustrate the key importance of the sampling algorithm: while the standard force field using TREx is in poor agreement with the NMR J-coupling and nuclear Overhauser effect and 2D FRET data, when using the TCW method, the standard and optimized protein-water force field combinations are in very good agreement with the same experimental data since the TCW sampling method produces qualitatively different ensembles than TREx. We also discuss the relative merit of the 2D FRET data when validating structural ensembles using the different force fields and sampling protocols investigated in this work for small IDPs such as the A beta 42 and A beta 43 peptides.