Abstract
It is generally accepted that oligomers of aggregating proteins play an important role in the onset of neurodegenerative diseases. While in silico aggregation studies of full length amyloidogenic proteins are computationally expensive, the assembly of short protein fragments derived from these proteins with similar aggregating properties has been extensively studied. In the present work, molecular dynamics simulations are performed to follow peptide aggregation on the microsecond time scale. By defining aggregation states, we identify transition networks, disconnectivity graphs, and first passage time distributions to describe the kinetics of the assembly process. This approach unravels differences in the aggregation into hexamers of two peptides with different primary structures. The first is GNNQQNY, a hydrophilic fragment from the prion protein Sup35, and the second is KLVFFAE, a fragment from amyloid-β protein, with a hydrophobic core delimited by two charged amino acids. The assembly of GNNQQNY suggests a mechanism of monomer addition, with a bias toward parallel peptide pairs and a gradual increase in the amount of β-strand content. For KLVFFAE, a mechanism involving dimers rather than monomers is revealed, involving a generally higher β-strand content and a transition toward a larger number of antiparallel peptide pairs during the rearrangement of the hexamer. The differences observed for the aggregation of the two peptides suggests the existence of a sequence-aggregation relationship.