Molecular modeling of two distinct triangular oligomers in amyloid beta-protein.

Amyloid-beta (Abeta) peptides exhibit many distinct structural morphology at the early aggregate stage, some of which are biological relevant to the pathogenesis of Alzheimer's disease (AD). Atomic-resolution structures of the early Abeta aggregates and their conformational changes in amyloid aggregation remain elusive. Here, we perform all-atom molecular modeling and dynamics simulations to obtain two stable triangular-like Abeta structures with the lowest packing energy, one corresponding to the Tycko's model (Paravastu, A.; Leapman, R.; Yau, W.; Tycko, R. Proc. Nat. Acad. Soc. U.S.A. 2008, 105, 18349-18354) (referred to C-WT model) and the other corresponding to computational model (N-WT model). Both models have the same 3-fold symmetry but distinct beta-sheet organizations in which three Abeta hexamers pack together via either C-terminal beta-strand residues or N-terminal beta-strand residues forming distinct hydrophobic cross section. Structural and energetic comparisons of two 3-fold Abeta oligomers, coupled with structural changes upon the mutations occurring at the interacting interfaces, reveal that although hydrophobic interactions are still dominant forces, electrostatic interactions are more favorable in the N-WT model due to the formation of more and stable intersheet salt bridges, while solvation energy is more favorable in the C-WT model due to more exposed hydrophilic residues to solvent. Both models display many common features similar to other amyloid oligomers and therefore are likely to be biologically relevant.