Exploring the molecular basis of UG‐rich RNA recognition by the human splicing factor TDP‐43 using molecular dynamics simulation and free energy calculation

RNA剪接 分子动力学 核糖核酸 突变体 分子力学 突变 生物物理学 化学 细胞生物学 RNA结合蛋白 基因 生物化学 生物 计算化学
作者
Han Sun,Wei Chen,Lin Chen,Wenqing Zheng
出处
期刊:Journal of Computational Chemistry [Wiley]
卷期号:42 (23): 1670-1680 被引量:12
标识
DOI:10.1002/jcc.26704
摘要

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.
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