Molecular dynamics simulation of the aggregation of the core-recognition motif of the islet amylolid 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-NFGAILCOOH peptide, the core-recognition motif of the type H
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. (c) 2005 Wiley-Liss,
Inc.