pH-Dependent interactions of human islet amyloid polypeptide segments with insulin studied by replica exchange molecular dynamics simulations.

Amyloidogenesis of human islet amyloid polypeptide (hIAPP) within or surrounding secretory beta-cells of pancreas has long been related to the pathology of type II diabetes. Insulin, coexpressed and cosecreted with hIAPP in vivo, has the capacity of interacting with hIAPP and further inhibiting the amyloid deposition of the peptide. On the basis of the reported experimental data, we conducted replica exchange molecular dynamics simulations on the complexes of insulin and the binding segment 9-20 of rat/human IAPP under different pH values. The deprotonation of H18 at neutral pH reduces the possibility of polar interactions at position 18 as well as the flanking positions. Moreover, it destabilizes the helical motif of insulin-bound hIAPP. From several perspectives, hIAPP with charged H18 bears more resemblance to rat IAPP (rIAPP) with a point mutation of R18 than its neutral version does. It is likely that the positively charged residue at position 18 is critical to insulin binding. At neutral pH, three loosely binding sites can be recognized on the insulin surface, while at acidic pH one dominant binding site is resolved, which is similar to the previously identified rIAPP-insulin binding site. Several critical intermolecular contacts, including salt-bridges and pi-stacking interactions, identified in the current study, could be used as the starting point for devising a potent peptide inhibitor of hIAPP amyloidogenesis.