Investigating the mechanism of peptide aggregation: Insights from mixed Monte Carlo-Molecular dynamics simulations

The early stages of peptide aggregation are currently not accessible by
experimental techniques at atomic resolution. In this article, we
address this problem through the application of a mixed simulation
scheme in which a preliminary coarse-grained Monte Carlo analysis of the
free-energy landscape is used to identify representative conformations
of the aggregates and subsequent all-atom molecular dynamics simulations
are used to analyze in detail possible pathways for the stabilization of
oligomers. This protocol was applied to systems consisting of multiple
copies of the model peptide GNNQQNY, whose detailed structures in the
aggregated state have been recently solved in another study. The
analysis of the various trajectories provides dynamical and structural
insight into the details of aggregation. In particular, the simulations
suggest a hierarchical mechanism characterized by the initial formation
of stable parallel beta-sheet dimers and identify the formation of the
polar zipper motif as a fundamental feature for the stabilization of
initial oligomers. Simulation results are consistent with experimentally
derived observations and provide an atomically detailed view of the
putative initial stages of fibril formation.