Simulations of Oligomeric Intermediates in Prion Diseases

Details Simulations of Oligomeric Intermediates in Prion Diseases Simulations of Oligomeric Intermediates in Prion Diseases

2003-07-09

arxiv.org/abs/physics/0307051v1

Biophys. J. 85:2213-2223 (Oct. 2003)

Physics

Biological Physics

8 pages, 10 figures For larger versions of several figures, see http://asaph.ucdavis.edu/~dmobley and click on the prion paper

Scientific paper

10.1016/S0006-3495(03)74647-5

We extend our previous stochastic cellular automata based model for areal aggregation of prion proteins on neuronal surfaces. The new anisotropic model allow us to simulate both strong beta-sheet and weaker attachment bonds between proteins. Constraining binding directions allows us to generate aggregate structures with the hexagonal lattice symmetry found in recently observed in vitro experiments. We argue that these constraints on rules may correspond to underlying steric constraints on the aggregation process. We find that monomer dominated growth of the areal aggregate is too slow to account for some observed doubling time-to-incubation time ratios inferred from data, and so consider aggregation dominated by relatively stable but non-infectious oligomeric intermediates. We compare a kinetic theory analysis of oligomeric aggregation to spatially explicit simulations of the process. We find that with suitable rules for misfolding of oligomers, possibly due to water exclusion by the surrounding aggregate, the resulting oligomeric aggregation model maps onto our previous monomer aggregation model. Therefore it can produce some of the same attractive features for the description of prion incubation time data. We propose experiments to test the oligomeric aggregation model.

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