Recent computational studies of membrane interaction and disruption of human islet amyloid polypeptide: Monomers,...

The amyloid deposits of human islet amyloid polypeptide (hIAPP) are found in type 2 diabetes patients. hIAPP monomer is intrinsically disordered in solution, whereas it can form amyloid fibrils both in vivo and in vitro. Extensive evidence suggests that hIAPP causes the disruption of cellular membrane, and further induces cytotoxicity and the death of islet β-cells in pancreas. The presence of membrane also accelerates the hIAPP fibril formation. hIAPP oligomers and protofibrils in the early stage of aggregation were reported to be the most cytotoxic, disrupting the membrane integrity and giving rise to the pathological process. The detailed molecular mechanisms of hIAPP-membrane interactions and membrane disruption are complex and remain mostly unknown. Here in this review, we focus on recent computational studies that investigated the interactions of full length and fragmentary hIAPP monomers, oligomers and protofibrils with anionic, zwitterionic and mixed anionic-zwitterionic lipid bilayers. We mainly discuss the binding orientation of monomers at membrane surface, the conformational ensemble and the oligomerization of hIAPP inside membranes, the effect of lipid composition on hIAPP oligomers/protofibrils-membrane interactions, and the hIAPP-induced membrane perturbation. This review provides mechanistic insights into the interactions between hIAPP and lipid bilayers with different lipid composition at an atomistic level, which is helpful to understand the hIAPP cytotoxicity mediated by membrane. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.