The aberrant self-assembly of human islet amyloid polypeptide (hIAPP) into toxic oligomers, protofibrils, and mature fibrils is associated with the pathogenesis of type 2 diabetes (T2D). Inhibition of hIAPP aggregation and destabilization of preformed hIAPP fibrils are considered as two major therapeutic strategies for treating T2D. Previous experimental studies reported that dopamine prevented the formation of hIAPP oligomers and fibrils. However, the underlying inhibitory mechanism at the atomic level remains elusive. Herein we investigated the conformational ensembles of hIAPP dimer with and without dopamine using replica-exchange molecular dynamics simulations. The simulations demonstrated that dopamine preferentially bound to R11, L12, F15, H18, F23, I26, L27, and Y37 residues, inhibited the formation of β-sheets in the amyloidogenic regions spanning residues 11RLANFLVH18, 22NFGAIL27, and 30TNVGSNT36, and resulted in more disordered hIAPP dimers, thus hindering the amyloid formation of hIAPP. Protonated and deprotonated dopamine molecules displayed distinct binding capabilities but bound to similar residue sites on hIAPP. Additional microsecond molecular dynamics simulations showed that dopamine mainly bound to the β1 and turn regions of hIAPP protofibril and destabilized the protofibril structure. This study not only revealed the molecular mechanism of dopamine toward the inhibition of hIAPP aggregation but also demonstrated the protofibril-destabilizing effects of dopamine, which may be helpful for the design of drug candidates to treat T2D.
Keywords: destabilization; dopamine; human islet amyloid polypeptide; inhibitory mechanism; protein aggregation; replica exchange molecular dynamics simulations.