Molecular insights into the inhibitory mechanism of rifamycin SV against β₂-microglobulin aggregation: A molecular...

Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic β₂-microglobulin (β₂m) protein around skeletal joints and bones. The small molecules that modulate β₂m aggregation have been identified in vitro, however, the underlying inhibitory mechanism remain elusive. In the present study, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of an antibiotic, rifamycin SV (C₁) reported for its in vitro anti-aggregation activity against β₂m. The molecular docking analysis highlight that C₁ display hydrophobic contacts with residues in the aggregation prone region of β₂m. MD simulations reveal enhanced structural stability of β₂m in the presence of C₁. C₁ inhibit the conformational transition of the C-terminal region of β₂m from a β-sheet to random coil conformation, which is reported for the initiation of fibrillogenesis of β₂m. The results of the present study provide insight into the key interactions and underlying inhibitory mechanism of a small molecule against β₂m aggregation that will help in the design and development of more potent, novel inhibitors of β₂m aggregation.