Spontaneous formation of oligomers and fibrils in large scale molecular dynamics simulations of peptides

Abstract

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. Fibrillization kinetics depends strongly on the temperature. Nucleation and templated growth via monomer addition occur at and near a transition temperature above which fibrils are unlikely to form. Oligomeric merging and structural rearrangement are observed at lower temperatures. We also examine the influence of crowding agents on oligomerization and fibrillization. Structural details of the fibrillar structures formed by the shorter peptides including intra-strand and inter-sheet distance and structure and the dependence of twist on the number of layers are consistent with those from experiments. Movies of the aggregation process on a molecular level will be shown.