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
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.