Akisumi Okamoto

Effect of D23N mutation on the dimer conformation of amyloid β-proteins: Ab initio molecular simulations in water

The molecular pathogenesis of Alzheimers disease (AD) is deeply involved in aggregations of amyloid β-proteins (Aβ) in a diseased brain. The recent experimental studies indicated that the mutation of Asp23 by Asn (D23N) within the coding sequence of Aβ increases the risk for the pathogeny of cerebral amyloid angiopathy and early-onset familial ADs. Fibrils of the D23N mutated Aβs can form both parallel and antiparallel structures, and the parallel one is considered to be associated with the pathogeny. However, the structure and the aggregation mechanism of the mutated Aβ fibrils are not elucidated at atomic and electronic levels. We here investigated solvated structures of the two types of Aβ dimers, each of which is composed of the wild-type or the D23N mutated Aβ, using classical molecular mechanics and ab initio fragment molecular orbital (FMO) methods, in order to reveal the effect of the D23N mutation on the structure of Aβ dimer as well as the specific interactions between the Aβ monomers. The results elucidate that the effect of the D23N mutation is significant for the parallel structure of Aβ dimer and that the solvating water molecules around the Aβ dimer have significant contribution to the stability of Aβ dimer.

Ab initio fragment molecular orbital calculations on the specific interactions between amyloid-β peptides in an in vivo amyloid-β fibril

The accumulation of amyloid-beta (Aβ) fibrils in a brain has been recognized to contribute to the onset of Alzheimers disease (AD). However, the relation between the structure of the aggregate and its toxicity to AD patients remains to be fully elucidated. A recent solid-state NMR analysis for the tissue obtained from the brains of AD patients revealed that the Aβ aggregates have only a single structure with three-fold symmetry. We here investigate the specific interactions between Aβ peptides in the aggregate, using ab initio fragment molecular orbital calculations, to explain why such a unique structure possesses significant stability. The results indicate that the interactions between the Aβ peptides of the stacked Aβ pair are stronger than those between the Aβ peptides of the trimer with three-fold symmetry. Furthermore, it is elucidated that the charged amino-acid residues of Aβ mainly contribute to the strong attractive interactions between the paired Aβ peptides.

Proposal for an inhibitor of Alzheimer's disease blocking aggregation of amyloid-β peptides: ab initio molecular simulations

Aggregation of amyloid-β (Aβ) peptides is believed to play a key role in the mechanism of molecular pathogenesis of Alzheimers disease (AD). To inhibit the aggregation and prevent AD, numerous compounds have been synthesized. A previous experimental study elucidated that a triazine derivative AA3E2 has anti-amyloidogenic ability, while a triazine derivative AA3D2 having a different substituent has no inhibitory effect. However, the reason for this remarkable difference in the ability cannot be explained by the chemical structures of these derivatives. In the present study, we present stable structures of the solvated complexes with Aβ and AA3E2/AA3D2 obtained by classical molecular mechanics method. The specific interactions between Aβ and AA3E2/AA3D2 in the complexes are investigated by ab initio fragment molecular orbital calculations. Based on the results obtained, we attempt to propose new potent inhibitors for the Aβ aggregation.

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 Alzheimers disease (AD). Recently, solid state NMR analysis for the tissues obtained from AD patients 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.