Molecular insights into the inhibitory mechanism of rifamycin SV against β2–microglobulin aggregation: A molecular dynamics simulation study

Abstract

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.