Molecular Modeling of Two Distinct Triangular Oligomers in Amyloid β-protein

Arnyloid-beta (A beta) 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 A beta 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 A beta 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 A beta 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 A beta 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.