Theoretical evaluation of a bulky -thioalkyl-azobenzene as an alternative to photocontrol structural cytotoxic effects of metal-free and disulfide oxidized hSOD1 in pathogenesis of ALS.

This study presents a novel photopharmacological strategy to mitigate the cytotoxic effects of apo-hSOD1, a misfolded protein implicated in neurodegenerative diseases. Using quantum chemical calculations and molecular dynamics simulations, we demonstrate that -thio-substituted azobenzene photoswitches (-TABPs) can be employed to precisely modulate the dynamics of the crucial electrostatic loop (EL) in apo-hSOD1. We establish that larger -alkyl substituents on the -TABP enhance its redox stability, favouring the conformation through the modulation of the position of the → π* transition. This stability is crucial for operation within the reducing cellular environment. Furthermore, we demonstrate the successful and consistent photomodulation of EL conformational dynamics in apo-hSOD1 through covalent tethering of an -TABP. This control is achieved by leveraging the thermodynamically stable conformation of the photoswitch, which allosterically influences the EL and consequently, the geometry of the Zn-binding site, a critical determinant of apo-hSOD1 cytotoxicity. This work paves the way for developing targeted therapies for neurodegenerative diseases by demonstrating the precise and effective photomodulation of apo-hSOD1 rationally designed -TABPs.