Alloform-specific differences in structural dynamics between Aβ40 and Aβ42 appear to underlie the pathogenesis of Alzheimer’s disease. To elucidate these differences, we performed µs time-scale replica exchange molecular dynamics simulations to sample the conformational space of the Aβ monomer and constructed its free energy surface. We find that neither peptide monomer is unstructured, but rather that each may be described as a unique statistical coil in which five relatively independent folding units exist, comprising residues 1–5, 10–13, 17–22, 28–37, and 39–42, which are connected by four turn structures. The free energy surfaces of both peptides are characterized by two large basins, comprising conformers either with substantial α-helix or β-sheet content. Conformational transitions within and between these basins are rapid. The two additional hydrophobic residues at the Aβ42 C-terminus, Ile41 and Ala42, significantly increase contacts within the C-terminus and between the C-terminus and the central hydrophobic cluster (Leu17-Ala21). As a result, the β-structure of Aβ42 is more stable than that of Aβ40 and the conformational equilibrium in Aβ42 shifts towards β-structure. These results suggest that drugs stabilizing α-helical Aβ conformers (or destabilizing the β-sheet state) would block formation of neurotoxic oligomers. The atomic-resolution conformer structures determined in our simulations may serve as useful targets for this purpose. The conformers also provide starting points for simulations of Aβ oligomerization, a process postulated to be the key pathogenetic event in AD.
Oligomerization of the amyloid β-protein (Aβ) is a seminal event in Alzheimer’s disease (AD). Aβ42, which is only two amino acids longer than Aβ40, is particularly pathogenic. Why this is so has not been elucidated fully. We report here results of computational and experimental studies revealing a C-terminal turn at Val36-Gly37 in Aβ42 that is not present in Aβ40. The dihedral angles of residues 36 and 37 in an Ile31–Ala42 peptide were consistent with β-turns, and a β-hairpin-like structure was indeed observed that was stabilized by hydrogen bonds and by hydrophobic interactions between residues 31–35 and residues 38–42. In contrast, Aβ(31–40) mainly existed as a statistical coil. To study the system experimentally, Aβ peptides containing amino acid substitutions designed to stabilize or destabilize the hairpin were chemically synthesized. The triple substitution Gly33Val–Val36Pro–Gly38Val (“VPV”) facilitated Aβ42 hexamer and nonamer formation, while inhibiting formation of classical amyloid-type fibrils. These assemblies were as toxic as were assemblies from wild type Aβ42. When substituted into Aβ40, the VPV substitution caused the peptide to oligomerize similarly to Aβ42. The modified Aβ40 was significantly more toxic than Aβ40. The double substitution D-Pro36-L-Pro37 abolished hexamer and dodecamer formation by Aβ42 and produced an oligomer size distribution similar to that of Aβ40. Our data suggest that the Val36-Gly37 turn could be the sine qua non of Aβ42. If true, this structure would be an exceptionally important therapeutic target.
wileyonlinelibrary.comsuch as transistor, [ 5 ] triboelectric, [ 6 ] capacitive, [ 7,8 ] piezoelectric, [9][10][11] and piezoresistive properties.Piezoresistive pressure sensors, which transform an input force into an electrical signal caused by the change in the resistance, have attracted considerable attentions by virtue of its simplicity and low cost in design and implementation. Most fl exible piezoresistive sensors are prepared by loading conductive nanomaterials (e.g., carbon nanotubes (CNTs), [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] graphene, [29][30][31][32] nanowires, [33][34][35] nanoparticles) onto fl exible substrates (e.g., fi bers, [ 12,13 ] fi lms, [14][15][16][17] opencell foams [ 29 ] ) via a number of processing methods, such as blending, [ 19,20 ] coating, [ 21,29 ] and printing. [ 17 ] Among the different conductive nanomaterials, carbon nanotubes have attracted a considerable amount of attention due to their remarkably high piezoresistive sensitivity. [ 36,37 ] In addition to the nanomaterials, which are the active sensing elements, the properties of the substrates also play a key role in determining the overall sensor performance. [ 27,28 ] Most studies on the effects of the substrates focus on the modulus, and it has been suggested that porous substrates with reduced elastic modulus result in increased sensing properties. [ 19 ] Yet from the classical mechanics point of view, the other most fundamental property that dictates the elastic properties is the Poisson ratio, which is defi ned as the ratio of the lateral contractile strain to the longitudinal tensile strain for a material undergoing tension in the longitudinal direction. Collectively, they defi ne the elastic properties and deformation characteristics of the materials in a 3D space. Conceivably, the Poisson ratio would impact the sensing performance of piezoresistive sensors; however, this effect has not been studied.Classical mechanics predicts that for isotropic materials, the Poisson ratio lies between -1 and 0.5, a fairly small range. [ 38 ] With a few exceptions such as α-cristobalite, [ 39 ] certain cubic metal, [ 40 ] and few biological tissues, [ 41 ] the range of Poisson ratio of almost all natural or synthetic materials is even smaller, typically 0.3-0.5. [ 42 ] Research on fabrication of auxetic materials or materials with negative Poisson ratios has progressed steadily since the initial report by Lakes [ 43 ] on the possibility of such materials. [ 44,45 ] The performance of fl exible and stretchable sensors relies on the optimization of both the fl exible substrate and the sensing element, and their synergistic interactions. Herein, a novel strategy is reported for cost-effective and scalable manufacturing of a new class of porous materials as 3D fl exible and stretchable piezoresistive sensors, by assembling carbon nanotubes onto porous substrates of tunable Poisson ratios. It is shown that the piezoresistive sensitivity of the sensors increases as the substrate's Poisson's ratio decrease...
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