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

• We elucidate the effect of D23N mutation on Aβ(15–40) dimer conformation in water.
• Stable conformations of the wild-type and mutated Aβ(15–40) dimer are investigated.
• Specific interactions between Aβ monomers are investigated by fragment MO method.
• D23N mutation has significant effect on the stability of the parallel Aβ dimer.
• The effect of D23N mutation on the stability of the antiparallel Aβ dimer is small.

The molecular pathogenesis of Alzheimer's 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.

By the D23N mutation, the salt bridge between Asp23 and Lys28 in the parallel conformation Aβ dimer is disappeared, resulting in a large reduction of the stability of the parallel conformation. Green dot-lines indicate the salt bridge.Figure optionsDownload high-quality image (219 K)Download as PowerPoint slide