Charge-Driven Fibril Recognition and Covalent Disruption of Aβ42 by Paddlewheel Diruthenium Complexes

Abstract The inhibition of Aβ42 (β-amyloid) fibril formation is a key therapeutic strategy in Alzheimer’s disease research. Paddlewheel diruthenium complexes have shown promising activity against Aβ42 aggregation and preformed fibril disaggregation, yet their molecular mode of action remains poorly understood. In this work, we perform atomistic simulations to explore how charge modulation influences the interactions of three analogous paddlewheel diruthenium complexes, the parent neutral complex [Ru2Cl(D-p-FPhF)(O2CCH3)3], and its anionic [Ru2Cl2(D-p-FPhF)(O2CCH3)3]− and cationic [Ru2(D-p-FPhF)(O2CCH3)3]+ counterparts (D-p-FPhF– is the N,N′-bis(4-fluorophenyl)formamidinato ligand) with Aβ42. Our results indicate that electrostatic tuning governs binding affinity and the extent of interaction across the Aβ42 fibril surface. As the complexes’ charge changes from −1 to +1, the interaction pattern shifts from localized contacts to widespread, multi-site engagement encompassing key charged, aromatic, and hydrophobic regions of Aβ42. This enhanced binding correlates with longer-lived, thermodynamically stable interactions at the fibril interface, which effectively lower the free energy penalty for fibril disassembly. Overall, our findings propose a mechanism in which charge-dependent activation through ligand exchange enhances fibril recognition and promotes disruptive binding modes, demonstrating the potential of charge-tunable diruthenium complexes as therapeutic modulators of Aβ42 fibril stability.