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

Abstract

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.