Graduate School of Medical Life Science, Yokohama City University, Tsurumiku, Yokohama, Japan.
Medical Sciences Innovation Hub Program, RIKEN, Tsurumiku, Yokohama, Japan.
Adv Exp Med Biol. 2018;1105:237-258. doi: 10.1007/978-981-13-2200-6_15.
Small-angle X-ray scattering (SAXS) is an efficient experimental tool to measure the overall shape of macromolecular structures in solution. However, due to the low resolution of SAXS data, high-resolution data obtained from X-ray crystallography or NMR and computational methods such as molecular dynamics (MD) simulations are complementary to SAXS data for understanding protein functions based on their structures at atomic resolution. Because MD simulations provide a physicochemically proper structural ensemble for flexible proteins in solution and a precise description of solvent effects, the hybrid analysis of SAXS and MD simulations is a promising method to estimate reasonable solution structures and structural ensembles in solution. Here, we review typical and useful in silico methods for modeling three dimensional protein structures, calculating theoretical SAXS profiles, and analyzing ensemble structures consistent with experimental SAXS profiles. We also review two examples of the hybrid analysis, termed MD-SAXS method in which MD simulations are carried out without any knowledge of experimental SAXS data, and the experimental SAXS data are used only to assess the consistency of the solution model from MD simulations with those observed in experiments. One example is an investigation of the intrinsic dynamics of EcoO109I using the computational method to obtain a theoretical profile from the trajectory of an MD simulation. The other example is a structural investigation of the vitamin D receptor ligand-binding domain using snapshots generated by MD simulations and assessment of the snapshots by experimental SAXS data.
小角 X 射线散射（SAXS）是一种有效的实验工具，可用于测量溶液中大分子结构的整体形状。然而，由于 SAXS 数据的分辨率较低，因此来自 X 射线晶体学或 NMR 的高分辨率数据以及分子动力学（MD）模拟等计算方法对于基于原子分辨率的结构理解蛋白质功能是 SAXS 数据的补充。由于 MD 模拟为溶液中的柔性蛋白质提供了物理化学上合适的结构集合体，并精确描述了溶剂效应，因此 SAXS 和 MD 模拟的混合分析是一种很有前途的方法，可以估计溶液中合理的溶液结构和结构集合体。在这里，我们回顾了用于建模三维蛋白质结构、计算理论 SAXS 曲线和分析与实验 SAXS 曲线一致的集合结构的典型和有用的计算方法。我们还回顾了两种混合分析的示例，称为 MD-SAXS 方法，其中 MD 模拟是在没有任何实验 SAXS 数据知识的情况下进行的，并且仅使用实验 SAXS 数据来评估 MD 模拟与实验中观察到的溶液模型的一致性。一个示例是使用计算方法研究 EcoO109I 的固有动力学，从 MD 模拟的轨迹中获得理论曲线。另一个示例是使用 MD 模拟生成的快照和实验 SAXS 数据评估快照来研究维生素 D 受体配体结合域的结构。
