Abstract
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 physico-chemical 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.
Highlights
The aggregation of soluble peptides and proteins first into soluble oligomeric assemblies and into insoluble amyloid fibrils is associated with the onset of misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, type II diabetes and transmissible spongiform encephalopathies [1,2,3,4,5]
While oligomers are considered as primary toxic species for most neurodegenerative diseases, there is recent experimental evidence that fragmentation or breakage of fibrils can contribute to the kinetics of aggregation and the amyloid cytotoxicity itself [33,34]
Replica-Exchange Molecular Dynamics (REMD) replica exchange molecular dynamics (REMD) is a thermodynamical sampling method that requires the running of N MD trajectories in parallel at N different temperatures selected in order to optimize thermodynamical sampling [52]
Summary
The aggregation of soluble peptides and proteins first into soluble oligomeric assemblies and into insoluble amyloid fibrils is associated with the onset of misfolding diseases such as Alzheimer’s disease, Parkinson’s disease, type II diabetes and transmissible spongiform encephalopathies [1,2,3,4,5]. GNNQQNY, from the N-terminal prion-determining domain of the yeast protein Sup, is a paradigmatic example of a short sequence with the same properties as its corresponding full-length protein [35,36] These properties include an amyloid fibril with a core cross-b spine, Congo-red binding and a nucleated-growth aggregation process [35]. Computer simulations have proved useful complements to experiments for looking at the initial aggregation steps providing information, for example, about the presence of amorphous states in dynamic equilibrium with fibrillar and annular states [38,39,40,41] and the final steps of the polymerization-nucleation process [23,42] They can provide atomic-resolution insights into several factors, ranging from the effect of sequence variations on aggregation tendencies to information on the stability of
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