National Institute of Standards and Technology and Institute for Bioscience and Biotechnology Research, 9600 Gudelsky Drive, Rockville, MD, 20850, USA.
J Biomol NMR. 2019 Apr;73(3-4):117-139. doi: 10.1007/s10858-019-00236-6. Epub 2019 May 2.
Structural information about ribonucleic acid (RNA) is lagging behind that of proteins, in part due to its high charge and conformational variability. Molecular dynamics (MD) has played an important role in describing RNA structure, complementing information from both nuclear magnetic resonance (NMR), or X-ray crystallography. We examine the impact of the choice of the empirical force field for RNA structure refinement using cross-validation against residual dipolar couplings (RDCs) as structural accuracy reporter. Four force fields, representing both the state-of-the art in RNA simulation and the most popular selections in NMR structure determination, are compared for a prototypical A-RNA helix. RNA structural accuracy is also evaluated as a function of both density and nature of input NMR data including RDCs, anisotropic chemical shifts, and distance restraints. Our results show a complex interplay between the experimental restraints and the force fields indicating two best-performing choices: high-fidelity refinement in explicit solvent, and the conformational database-derived potentials. Accuracy of RNA models closely tracks the density of 1-bond C-H RDCs, with other data types having beneficial, but smaller effects. At lower RDC density, or when refining against NOEs only, the two selected force fields are capable of accurately describing RNA helices with little or no experimental RDC data, making them available for the higher order structure assembly or better quantification of the intramolecular dynamics. Unrestrained simulations of simple RNA motifs with state-of-the art MD force fields appear to capture the flexibility inherent in nucleic acids while also maintaining a good agreement with the experimental observables.
RNA 的结构信息落后于蛋白质，部分原因是其高电荷和构象可变性。分子动力学（MD）在描述 RNA 结构方面发挥了重要作用，补充了来自核磁共振（NMR）或 X 射线晶体学的信息。我们通过与残基偶极耦合（RDC）交叉验证来检查选择 RNA 结构精修经验力场对结构准确性的影响，RDC 作为结构准确性的报告者。我们比较了四种力场，它们代表了 RNA 模拟的最新技术和 NMR 结构测定中最受欢迎的选择，用于典型的 A-RNA 螺旋。还根据输入 NMR 数据的密度和性质（包括 RDC、各向异性化学位移和距离约束）评估 RNA 结构的准确性。我们的结果表明实验约束和力场之间存在复杂的相互作用，表明有两个表现最佳的选择：在明水环境中进行高保真度精修，以及基于构象数据库的势。RNA 模型的准确性与 1 键 C-H RDC 的密度密切相关，其他数据类型具有有益但较小的影响。在较低的 RDC 密度下，或者仅对 NOE 进行精修时，这两种选定的力场能够准确描述具有很少或没有实验 RDC 数据的 RNA 螺旋，使其可用于更高阶结构组装或更好地定量分子内动力学。使用最新的 MD 力场对简单 RNA 基元进行无约束模拟似乎可以捕捉到核酸固有的灵活性，同时与实验可观察结果保持良好的一致性。
