Molecular dynamics simulations of Alzheimer Abeta40 elongation and lateral association.

Amyloid-beta (Abeta) peptides can elongate in the fibril axis and associate in the lateral direction. We present detailed atomic Abeta models with different in-register intermolecular beta-sheet-beta-sheet associations. We probe structural stability, conformational dynamics, and association force of Abeta oligomers with various sizes and structures for both wild-type and mutated sequences using molecular dynamics (MD) simulations. MD simulations show that an Abeta oligomer that is laterally associated through the C-terminal-C-terminal interface is energetically more favorable than other oligomers with the N-terminal-N-terminal and C-terminal-N-terminal interfaces. We further develop a simple numerical model to describe the kinetics of Abeta aggregation process by considering fibril elongation and lateral association using a Monte Carlo algorithm. Kinetic data suggest that fibril elongation and lateral association are mutually competitive. Single-point mutations of Glu22 or Met35 at the interfaces have profound negative effects on intermolecular beta-sheet-beta-sheet association. These disease-related mutants (E22K, E22Q, and M35O) display more flexible structures, weaker lateral association, and stronger elongation tendencies than the wild type, suggesting that amyloid oligomerization and neurotoxicity might be linked to fibril longitudinal growth.