Molecular Dynamics Simulations Reveal the InhibitoryMechanism of Dopamine against Human Islet Amyloid Polypeptide (hIAPP)Aggregation and Its Destabilization Effect on hIAPP Protofibrils

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 atom 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 d...