College of Chemistry and Chemical Engineering, Qiqihar University, Qiqihar, China.
J Comput Chem. 2021 Sep 5;42(23):1670-1680. doi: 10.1002/jcc.26704. Epub 2021 Jun 9.
Transactivation response element RNA/DNA-binding protein 43 (TDP-43) is involved in the regulation of alternative splicing of human neurodegenerative disease-related genes through binding to long UG-rich RNA sequences. Mutations in TDP-43, most in the homeodomain, cause neurological disorders such as amyotrophic lateral sclerosis and fronto temporal lobar degeneration. Several mutants destabilize the structure and disrupt RNA-binding activity. The biological functions of these mutants have been characterized, but the structural basis behind the loss of RNA-binding activity is unclear. Focused on the specific TDP-43-ssRNA complex (PDB code 4BS2), we applied molecular dynamics simulations and the molecular mechanics Poisson-Boltzmann surface area free energy calculation to characterize and explore the structural and dynamic effects between ssRNA and TDP-43. The energetic analysis indicated that the intermolecular van der Waals interaction and nonpolar solvation energy play an important role in the binding process of TDP-43 and ssRNA. Compared with the wild-type TDP-43, the reduction of the polar or non-polar interaction between all the mutants F149A, D105A/S254A, R171A/D174A, F147L/F149L/F229L/F231L and ssRNA is the main reason for the reduction of its binding free energy. Decomposing energies suggested that the extensive interactions between TDP-43 and the nitrogenous bases of ssRNA are responsible for the specific ssRNA recognition by TDP-43. These results elucidated the TDP-43-ssRNA interaction comprehensively and further extended our understanding of the previous experimental data. The uncovering of TDP-43-ssRNA recognition mechanism will provide us useful insights and new chances for the development of anti-neurodegenerative drugs.
反式激活反应元件 RNA/DNA 结合蛋白 43（TDP-43）通过与富含 UG 的长 RNA 序列结合，参与人类神经退行性疾病相关基因的可变剪接调控。TDP-43 的突变，大多在同源域，导致神经紊乱，如肌萎缩性侧索硬化症和额颞叶变性。一些突变体破坏了结构并扰乱了 RNA 结合活性。这些突变体的生物学功能已经得到了描述，但 RNA 结合活性丧失的结构基础尚不清楚。我们专注于特定的 TDP-43-ssRNA 复合物（PDB 代码 4BS2），应用分子动力学模拟和分子力学泊松-玻尔兹曼表面自由能计算来描述和探索 ssRNA 与 TDP-43 之间的结构和动态效应。能量分析表明，分子间范德华相互作用和非极性溶剂化能在 TDP-43 和 ssRNA 的结合过程中起着重要作用。与野生型 TDP-43 相比，所有突变体 F149A、D105A/S254A、R171A/D174A、F147L/F149L/F229L/F231L 与 ssRNA 之间极性或非极性相互作用的减少是其结合自由能降低的主要原因。分解能量表明，TDP-43 与 ssRNA 含氮碱基之间的广泛相互作用是 TDP-43 特异性识别 ssRNA 的原因。这些结果全面阐明了 TDP-43-ssRNA 相互作用，进一步扩展了我们对先前实验数据的理解。揭示 TDP-43-ssRNA 识别机制将为开发抗神经退行性药物提供有用的见解和新机会。
