Effect of the Tottori Familial Disease Mutation (D7N) on the Monomers and Dimers of Aβ₄₀and Aβ₄₂

Abstract

ABSTRACT:Recent experiments have shown that the mutation Tottori (D7N) alters the toxicity, assembly and rate of fibril formation of the wild type (WT) amyloid beta (Aβ) Aβ 40 and Aβ 42 peptides. We used all-atom molecular dynamics simulations in explicit solvent of the monomer and dimer of both alloforms with their WT and D7N sequences. The monomer simulations starting from a random coil and totaling 3 μs show that the D7N mutation changes the fold and the network of salt bridges in both alloforms. The dimer simulations starting from the amyloid fibrillar states and totaling 4.4 μs also reveal noticeable changes in terms of secondary structure, salt bridge, and topology. Overall, this study provides physical insights into the enhanced rate of fibril formation upon D7N mutation and an atomic picture of the D7N-mediated conformational change on Aβ 40 and Aβ 42 peptides. KEYWORDS: Amyloid simulation, Alzheimer's disease, amyloid-β proteins, molecular dynamics, D7N mutation, monomer, dimer A lzheimer's disease (AD) is the most common form of dementia among the senior population.1 The patient with AD will lose memory, 2 decay language, 3 and experience problems with visual-spatial search, 4 among other side-effects. AD is pathologically characterized by brain lesions that are senile plaques made of the beta amyloid (Aβ) peptides 5 and neurofibrillary tangles inside neurons made of the tau protein. 6 However, there is strong evidence that the Aβ peptides play a central role in AD. 7,8 The Aβ peptides are proteolytic byproducts of the amyloid precursor protein and are most commonly composed of 40 (Aβ 40 ) and 42 (Aβ 42 ) amino acids. The Aβ monomers are mostly random coil in physiological buffers, but aggregate to form amyloid fibrils with a cross-β-sheet pattern. 9−11Presently, there are no efficient drugs against AD. One current strategy, based on the fact that the aesthetic of the cerebral defects in AD correlates with high levels of oligomers in the brain, 12,13 is to design molecules preventing amyloid fibril formation and targeting the early formed toxic aggregates. 5,7,14−18 The another strategy is to design molecules enhancing fibril formation and reducing therefore the lifetimes of Aβ oligomers. 19 Unfortunately, because these assemblies are in dynamic equilibrium, experiments have failed thus far to provide atomic structures that would help design more efficient molecules in both scenarios.Numerous pathogenic familial mutations are known to modulate fibril formation rates and enhance toxicity. There has been many experimental studies on the Flemish (A21G), Dutch (E22Q), Italian (E22K), Arctic (E22G), Iowa (D23N), and Osaka (ΔE22, deletion) variants. 20−25 The English (H6R), 26Taiwanese (D7H), 27 and Tottori (D7N) 28 mutations that cause early onset familial AD have also been reported. The English and Tottori mutations do not affect Aβ production, but they accelerate fibril assembly in the absence of increased protofibril formation.29 A more recent experimental study showed that the Tottori mutation alters ...

Effect of the English Familial Disease Mutation (H6R) on the Monomers and Dimers of Aβ40 and Aβ42

“…It should be stressed that the results obtained for all WT systems have been already reported in our previous work, 43 but we show them again to better clarify the effect of H6R mutation on structural dynamics and assembly dynamics.…”

“…The similar effect on turn, coil and β-structure was obtained by the Tottori familial disease mutation (D7N). 43 To obtain more details on the impact of H6R on Aβ 40 and Aβ 42 monomers, one considers the secondary structure propensity along the sequence (Figure 2). While the averaged contents over all residues are rather similar for both Aβ 40 species, the perresidue propensities differ for β-strand, α-helix, turn, and coil.…”

“…42 The impact of D7N on the aggregation and structure dynamics of alloforms Aβ 40 and Aβ 42 has been studied in our previous simulations. 43 In this paper, a similar study is conducted but for the English mutation H6R using all-atom MD simulations at 300 K in explicit solvent within the microsecond time scale. Our goal is to understand at the atomistic level the influence of this mutation on random coil monomeric structures and fibrillar-like dimeric structures of Aβ 40 and Aβ 42 .…”

“…The data sampling WT systems was described previously. 43 Upon mutation, the β-structure decreases from 32% in 2Aβ 40 -WT to 15% in 2Aβ 40 -H6R (Table 1). The reduction takes place at residues 13−20 and 31−35, whereas the visible enhancement occurs at residues 6, 10, and 39 ( Figure 4).…”

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

“…For H6R, the reduction in the net charge was found to be a major contributor to enhancing aggregation; however, the mutation also caused an increase in hydrophobicity, and this compounded the issue 9. D7N was shown to change the fold and salt‐bridge network within the peptide 10. Furthermore, these mutations can significantly increase the solvation free energy and thus enhance the aggregation of Aβ monomers 11…”