hIAPP-Amyloid-Core Derived d-Peptide Prevents hIAPP Aggregation and Destabilizes Its Protofibrils

The aberrant misfolding of human islet amyloid polypeptide into cytotoxic amyloid aggregates is the hallmark of type II diabetes. In order to avert the formation of amyloid aggregation, a variety of peptides has been used as inhibitors. Recently, a peptide derived from the amyloidogenic core of hIAPP (hIAPP22–27) and consisting of all d-amino acid residues (D-nl), was found to efficiently prevent hIAPP fibril formation. To investigate the mechanism via which D-nl inhibits hIAPP aggregation, we have carried out all-atom molecular dynamics simulations, where we observe that the ordered β-sheet structure of hIAPP22–27 is completely destabilized when D-nl is incorporated in it. The formation of β-sheet structures by full-length hIAPP is also not favored in the presence of D-nl peptides, due to which hIAPP tends to attain a random loosely packed conformation. As a control, we also study the influence of hIAPP22–27 (L-nl) on the aggregation propensity of full length hIAPP. While L-nl supports the aggregation of hIAPP by stabilizing the β-sheet rich aggregates, D-nl interrupts hIAPP–hIAPP interactions via hydrogen bonding and hydrophobic interactions, thus obstructing the self-aggregation of hIAPP. Further, D-nl also partially dissolves the preformed hIAPP protofibrils. This work provides new insight into the activity of peptide inhibitors against amyloid aggregation at a molecular level and can be exploited to advance the field of diabetes treatment.