Abstract
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.
Users
Please
log in to take part in the discussion (add own reviews or comments).