Aggregation of intrinsically disordered proteins plays an important role in the pathogenesis of a number of neurodegenerative diseases. To explore the early stages of nucleation we conducted all atom simulations in explicit solvent of an amyloidogenic peptide derived from the non-amyloid-β component of α-synuclein.  Simulations 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.  From these data we derive a model for the nucleation of amyloidogenic peptides where β-sheets form in a stepwise manner via the association of extended monomers arising from unfolding of a dynamic helical oligomer. Secondly, to explore factors that affect the process of fibril growth we computed the free energy associated with disordered Amyloid-β (Aβ) monomers being added to growing amyloid fibrils using extensive molecular dynamics simulations coupled with umbrella sampling. We find that the mechanism of Aβ fibril elongation includes the formation of an obligate on-pathway β-hairpin intermediate that hydrogen bonds to the fibril core.  In addition, these data lead to new hypotheses as to how fibrils may serve as secondary nucleation sites that can catalyze the formation of soluble oligomers – a finding in agreement with recent experimental observations.  In sum, these observations provide a detailed mechanistic description of fundamental processes underlying the formation of pathogenic neurotoxic aggregates.

Aggregation mechanism of amyloidogenic proteins involved in neurodegenerative disorders

249th National Meeting (2015)

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