Molecular dynamics and ab initio molecular orbital calculations on conformational change of amyloid-β monomers in an in vivo amyloid-β nonamer

The accumulation of amyloid beta (A beta) oligomers and fibrils in a brain is deeply involved as a major cause of the onset of Alzheimer's disease (AD). Recently, solid state NMR analysis for the tissues obtained from AD patient's brain has revealed that A beta aggregates in the tissues have a single patient-specific structure with three-fold symmetry. However, the relationship between the structure of accumulated A beta s and its toxicity to AD patients has not been fully elucidated. This three-fold symmetry structure is markedly different from those of the in vitro A beta fibrillar models. To clarify why this structure has significant stability, we here investigate the change in conformation of each A beta peptide in the aggregates, using classical molecular dynamics (MD) simulations in water. Additionally ab initio fragment molecular orbital calculations are carried out for several structures obtained by the MD simulations to elucidate the specific interactions between A beta peptides in the aggregates. The results simulated demonstrate that the interactions between the A beta peptides which form stock the A beta pairs are stronger than those between the A beta peptides of trimers having three-fold symmetry in each layer. In addition, the charged amino-acid residues of A beta peptide are found to contribute mainly to the significant stability of the A beta aggregate.