Molecular dynamics simulations to explore the binding mode between the amyloid-β protein precursor (APP) and adaptor protein Mint2.

Alzheimer's disease (AD) presents a significant challenge in neurodegenerative disease management, with limited therapeutic options available for its prevention and treatment. At the heart of AD pathogenesis is the amyloid-β (Aβ) protein precursor (APP), with the interaction between APP and the adaptor protein Mint2 being crucial. Despite previous explorations into the APP-Mint2 interaction, the dynamic regulatory mechanisms by which Mint2 modulates APP binding remain poorly understood. This study undertakes molecular dynamics simulations across four distinct systems-free Mint2, Mint2 bound to APP, a mutant form of Mint2, and the mutant form bound to APP-over an extensive 400 ns timeframe. Our findings reveal that the mutant Mint2 experiences significant secondary structural transformations, notably the formation of an α-helix in residues S55-K65 upon APP binding, within the 400 ns simulation period. Additionally, we observed a reduction in the active pocket size of the mutant Mint2 compared to its wild-type counterpart, enhancing its APP binding affinity. These insights hold promise for guiding the development of novel inhibitors targeting the Mints family, potentially paving the way for new therapeutic strategies in AD prevention and treatment.