A Multiscale Approach to Characterize the Early Aggregation Steps of the Amyloid-Forming Peptide GNNQQNY from the Yeast Prion Sup-35

The self-organization of peptides into amyloidogenic oligomers is one of
the key events for a wide range of molecular and degenerative diseases.
Atomic-resolution characterization of the mechanisms responsible for the
aggregation process and the resulting structures is thus a necessary
step to improve our understanding of the determinants of these
pathologies. To address this issue, we combine the accelerated sampling
properties of replica exchange molecular dynamics simulations based on
the OPEP coarse-grained potential with the atomic resolution description
of interactions provided by all-atom MD simulations, and investigate the
oligomerization process of the GNNQQNY for three system sizes: 3-mers,
12-mers and 20-mers. Results for our integrated simulations show a rich
variety of structural arrangements for aggregates of all sizes.
Elongated fibril-like structures can form transiently in the 20-mer
case, but they are not stable and easily interconvert in more globular
and disordered forms. Our extensive characterization of the intermediate
structures and their physicochemical determinants points to a high
degree of polymorphism for the GNNQQNY sequence that can be reflected at
the macroscopic scale. Detailed mechanisms and structures that underlie
amyloid aggregation are also provided.