Mechanistic elucidation and inhibition of the pathogenic aberrant mitochondrial localization of the RNA/DNA-binding protein, TDP-43, can help in the therapeutics of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). A mitochondrial localization sequence of TDP-43, M1, is largely solvent inaccessible; therefore, how it interacts with the mitochondrial import machinery to facilitate TDP-43's transit to mitochondria is unclear. Towards this, we examined the unfolding TDP-43's N-terminal domain (NTD) that hosts M1, using equilibrium all-atom molecular dynamics (MD) simulations, and observed an early loss of the hydrogen-bonded interactions between {beta}4 and {beta}5 bridge and the interactions involving residues Phe-35 and Gly-40 of M1, indicating structural lability of M1 to become solvent-accessible that may enhance its interaction with the mitochondrial receptor(s) for import. Furthermore, via virtual screening of 2,115 FDA-approved and 515,545 non-FDA-approved small molecules from the ZINC15 database towards binding to M1 and inhibiting TDP-43's mitochondrial import, we identified a molecule, ZINC73240059, that was previously characterized as an inhibitor of MAP kinase-activating protein kinase 2 (MAPKAPK2). ZINC73240059 remains stably bound to M1 of NTD during MD simulations, manifesting negative Gibbs free energy ({Delta}G) with significant contribution from Pro-36 of M1. Overall, ZINC73240059 can be a molecule of interest towards thwarting TDP-43's pathogenic mitochondrial localization in ALS.
Balaji, R., Bhardwaj, S., Baa, J., Joshi, H., Patel, B. K.
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