Department of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, USA.
J Chem Phys. 2019 Mar 14;150(10):104108. doi: 10.1063/1.5078615.
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 Aβ42 and Aβ43, which both should be random coils as shown recently by experimental nuclear magnetic resonance (NMR) and 2D Förster 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 Aβ42 and Aβ43 peptides.
如果力场足够准确，并且模拟能够以正确的权重充分采样 IDP 的构象空间，那么对无规卷曲蛋白 (IDP) 的分子动力学模拟可以提供高分辨率的结构集合。在这里，我们通过测试标准力场和新的固定电荷力场来研究组合力场-采样问题，后者专门针对更好地描述展开状态和 IDP 而设计，并将它们与标准温度交换复制 (TREx) 协议和非平衡温度冷却行走 (TCW) 采样算法进行比较。使用力场和采样组合来表征淀粉样β肽 Aβ42 和 Aβ43 的结构集合，这两种肽都应该是无规卷曲，正如最近的实验核磁共振 (NMR) 和二维Förster 共振能量转移 (FRET) 实验所示。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 NMR J 耦合和核 Overhauser 效应和二维 FRET 数据的一致性很差，但当使用 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非常一致，因为 TCW 采样方法产生的集合与 TREx 不同。我们还讨论了在使用这项工作中研究的不同力场和采样方案验证小分子 IDP（如 Aβ42 和 Aβ43 肽）的结构集合时，二维 FRET 数据的相对优点。
