(395b) Spontaneous Formation of Oligomers and Fibrils in Large Scale Molecular Dynamics Simulations of Peptides

Protein aggregation is associated with serious and eventually-fatal neurodegenerative diseases including Alzheimer’s and Parkinson’s. While atomic resolution molecular dynamics simulations have been useful in this regard, they are limited to examination of either oligomer formation by a small number of peptides or analysis of the stability of a moderate number of peptides placed in trial or known experimental structures. We describe large scale intermediate-resolution molecular dynamics simulations of the spontaneous formation of fibrils by systems containing large numbers (48-96) of peptides including A-beta (16-22),( 17-42), (1-40) and (1-42) . We trace out the aggregation process from an initial configuration of random coils to oligomers and then to proto-filaments with cross-β structures and demonstrate how kinetics dictates the structural details of the fully formed fibril. Particular noteworthy are our simulation results for a system of 8 Aβ17-42 peptides. Protofilaments containing the U-shape β-sheet structures seen in solid state NMR experiments by the Tycko group  are realized in simulations starting from random chains, the first time that this has been observed computationally. We observe two different conformational conversion from disordered oligomers to ordered protofilament: (1) one-by-one monomeric conversion  to a fibrillar structure, and (2) very slow conversion of a meta-stable oligomer with “S”-shaped chains to a fibrillar structure. The relatively long life of the metastable S-shaped oligomers compared to that of the U-shaped oligomers that we see in our simulations suggests that S-shaped oligomers are likely to be toxic, as has been suggested in recent experiments by the Smith group. Movies of the aggregation process on a molecular level will be shown.