Chemistry Program, Science Division, New York University, P.O. Box 129188, Abu Dhabi, United Arab Emirates.
Department of Chemistry, New York University, New York, New York 10003United States.
J Phys Chem Lett. 2022 Apr 21;13(15):3400-3408. doi: 10.1021/acs.jpclett.2c00359. Epub 2022 Apr 11.
The growing recognition of the functional and therapeutic roles played by RNA and the difficulties in gaining atomic-level insights by experiments are paving the way for all-atom simulations of RNA. One of the main impediments to the use of all-atom simulations is the imbalance between the energy terms of the RNA force fields. Through exhaustive sampling of an RNA helix-junction-helix (HJH) model using enhanced sampling, we critically assessed the select Amber force fields against small-angle X-ray scattering (SAXS) experiments. The tested AMBER99SB, DES-AMBER, and CUFIX force fields show deviations from measured profiles. First, we identified parameters leading to inconsistencies. Then, as a way to balance the forces governing RNA folding, we adopted strategies to refine hydrogen bonding, backbone, and base-stacking parameters. We validated the modified force field (HB-CUFIX) against SAXS data of the HJH model in different ionic strengths. Moreover, we tested a set of independent RNA systems to cross-validate the force field. Overall, HB-CUFIX demonstrates improved performance in studying thermodynamics and structural properties of realistic RNA motifs.
越来越多的人认识到 RNA 具有功能和治疗作用，同时实验也难以提供原子水平的见解，这为 RNA 的全原子模拟铺平了道路。全原子模拟的主要障碍之一是 RNA 力场的能量项之间存在不平衡。通过使用增强采样对 RNA 螺旋-连接-螺旋（HJH）模型进行彻底采样，我们使用小角 X 射线散射（SAXS）实验对所选 Amber 力场进行了严格评估。测试的 Amber99SB、DES-AMBER 和 CUFIX 力场与测量的图谱存在偏差。首先，我们确定了导致不一致的参数。然后，作为平衡控制 RNA 折叠的力的一种方法，我们采用了改进氢键、主链和碱基堆积参数的策略。我们使用不同离子强度下 HJH 模型的 SAXS 数据对修改后的力场（HB-CUFIX）进行了验证。此外，我们还测试了一组独立的 RNA 系统来交叉验证力场。总体而言，HB-CUFIX 在研究现实 RNA 基序的热力学和结构特性方面表现出了更好的性能。
