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

The accumulation of amyloid beta (Aβ) 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 Aβ aggregates in the tissues have a single patient-specific structure with three-fold symmetry. However, the relationship between the structure of accumulated Aβs and its toxicity to AD patients has not been fully elucidated. This threefold symmetry structure is markedly different from those of the in vitro Aβ fibrillar models. To clarify why this structure has significant stability, we here investigate the change in conformation of each Aβ 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 Aβ peptides in the aggregates. The results simulated demonstrate that the interactions between the Aβ peptides which form stock the Aβ pairs are stronger than those between the Aß peptides of trimers having three-fold symmetry in each layer. In addition, the charged amino-acid residues of Aß peptide are found to contribute mainly to the significant stability of the Aβ aggregate.