Physical Mechanisms of Protofilament Formation

Protein misfolding and aggregation are associated with the onset of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease. To date no cure exists for neurodegenerative diseases and therapeutic interventions give limited symptomatic relief, rather than prevention. Prefibrillar aggregates (oligomers) are associated with neurotoxicity. A better understanding of the physicochemical properties that govern the assembly mechanism of the early oligomeric species will aid in understanding their role in toxic propagation.

Here, we introduce a novel coarse-grained model for amyloidogenic polypeptides [1] and use Brownian dynamic simulations [2] to gain insight into the physical mechanisms of assembly into oligomeric species. We find that spherical and elongated oligomers form via different mechanisms. The first are governed by hydrophobic interactions and grow mainly via monomer addition, while the latter additionally undergo structural modifications, frequent breakage and hierarchical assembly. Our results are complemented by atomic force microscopy measurements and explain experimental observations [3].

References

[1] B. Mayer et al. in preparation

[2] I.M. Ilie et al, J. Chem. Phys., 142, 114103 (2015)

[3] F.S. Ruggeri et al. PNAS, 115, 7231(2018)