Professor of Electrical Engineering and Computer Science, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, USA
The aggregation of α-synuclein into amyloid superstructures plays an important role in the pathogenesis of Parkinson’s disease. Aggregation in vitro occurs in two phases: a lag-phase, where nuclei that seed aggregation are formed, and a growth phase, where existing amyloid fibrils are elongated. In this study we explore the early stages of nucleation for a peptide that corresponds to the minimum fragment of α-synuclein that forms amyloid fibrils and that is neurotoxic in vitro. All atom molecular dynamics simulations in explicit solvent were notable for the rapid formation of a helical multimer that unfolds and refolds on the microsecond timescale. During unfolding, monomers in the oligomeric unit sample extended states consistent with a β-strand. Once one monomer in the oligomer is extended, adjacent monomers sample extended states with increased probability. From these data we derive a model for nucleation where β-sheets form in a stepwise manner via the association of extended monomers that arise from the unfolding of a dynamic helical oligomer. These observations provide new insights into early stages of the nucleation process and clarify experimental observations on the mechanism of α-synuclein aggregation.
Keywords: Aggregation, nucleation, nucleation, formation, fragment.