The Effect of Single and Double Acetylation of Lysine Residues on Structural and Dynamical Features of Human Splicing Factor TDP-43 - A Statistical Ensemble Analysis

Background: The acetylated inclusions containing TDP-43 are found in the spinal cord of amyotrophic lateral sclerosis (ALS) patients, suggesting that aberrant TDP-43 acetylation and resulting disruption of RNA binding are linked to onset and progression of TDP-43 proteinopathy. Methods: Here, the consequences of TDP-43 acetylation at Lys145 within the RRM1 domain and Lys192 within the RRM2 domain were studied using experimentally verifiable molecular models, in which lysine residues (K) were substituted with glutamine (Q) as an acetylation mimic (K→Q) and with arginine (R) as a non-mimic (K→R) mutant. We used a series of computer simulations to characterize the impact of lysine acetylation on TDP-43 function and TDP-43 association with target RNA. Results: Using snapshots collected from the MD simulation trajectories, the cross-correlation and principal component analyses (PCA) were applied to shed light on the dynamic discrepancy among the ten studied systems and to discern TDP-43 subdomains that exhibit conformational plasticity in response to acetylation mimic and non-mimic mutations. Moreover, we also investigated the global network parameter, betweenness, to model communication pathways and identify a network of critical mediating nodes involved in long-range signaling. These nodes describe the functionally significant TDP-43 residues involved in TDP-43 regulation. Conclusion: The identification of the critical nodes and optimal path mediating the dynamical network communication could offer new strategies to manipulate TDP-43 function. Disrupting a specific network communication could represent a rational approach to the design of drugs with improved potency and selectivity.