Molecular dynamics simulation of the aggregation of the core-recognition motif of the islet amyloid polypeptide in explicit water

The formation of amyloid fibrils is associated with major human diseases. Nevertheless, the molecular mechanism that directs the nucleation of these fibrils is not fully understood. Here, we used molecular dynamics simulations to study the initial self-assembly stages of the NH₂-NFGAIL-COOH peptide, the core-recognition motif of the type II diabetes associated islet amyloid polypeptide. The simulations were performed using multiple replicas of the monomers in explicit water, in a confined box starting from a random distribution of the peptides at T = 300 K and T = 340 K. At both temperatures the formation of unique clusters was observed after a few nanoseconds. Structural analysis of the clusters clearly suggested the formation of "flat" ellipsoid-shaped clusters through a preferred locally parallel alignment of the peptides. The unique assembly is facilitated by a preference for an extended conformation of the peptides and by intermolecular aromatic interactions. Taken together, our results may provide a description of the molecular recognition determinants involved in fibril formation, in terms of the atomic detailed structure of nascent aggregates. These observations may yield information on new ways to control this process for either materials development or drug design.