Dataset Information

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid ? Assemblies.

ABSTRACT: Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid ? (A?) oligomers in the brain of patients. Two principal variants of A? exist in humans: A?1-40 and A?1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of A?1-40 peptides can only assume U-shaped conformations while A?1-42 can also arrange as S-shaped three-stranded chains, as recently discovered. As alterations in protein conformational arrangement correlate with cell toxicity and speed of disease progression, it is important to characterize, at molecular level, the conformational dynamics of amyloid fibrils. In this work, Replica Exchange Molecular Dynamics simulations were carried out to compare the conformational dynamics of U-shaped and S-shaped A?17-42 small fibrils. Our computational results provide support for the stability of the recently proposed S-shaped model due to the maximized interactions involving the C-terminal residues. On the other hand, the U-shaped motif is characterized by significant distortions resulting in a more disordered assembly. Outcomes of our work suggest that the molecular architecture of the protein aggregates might play a pivotal role in formation and conformational stability of the resulting fibrils.

SUBMITTER: Grasso G

PROVIDER: S-EPMC5855793 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

Grasso Gianvito G Rebella Martina M Muscat Stefano S Morbiducci Umberto U Tuszynski Jack J Danani Andrea A Deriu Marco A MA

International journal of molecular sciences 20180214 2

Alzheimer's disease is the most fatal neurodegenerative disorder characterized by the aggregation and deposition of Amyloid β (Aβ) oligomers in the brain of patients. Two principal variants of Aβ exist in humans: Aβ1-40 and Aβ1-42. The former is the most abundant in the plaques, while the latter is the most toxic species and forms fibrils more rapidly. Interestingly, fibrils of Aβ1-40 peptides can only assume U-shaped conformations while Aβ1-42 can als ...[more]

PMID: 29443891

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Project description:Amyloid fibrils are associated with many neurodegenerative diseases. It was found that amyloidogenic oligomers, not mature fibrils, are neurotoxic agents related to these diseases. Molecular mechanisms of infectivity, pathways of aggregation, and molecular structure of these oligomers remain elusive. Here, we use all-atom molecular dynamics, molecular mechanics combined with solvation analysis by statistical-mechanical, three-dimensional molecular theory of solvation (also known as 3D-RISM-KH) in a new MM-3D-RISM-KH method to study conformational stability, and association thermodynamics of small wild-type Abeta(17-42) oligomers with different protonation states of Glu(22), as well the E22Q (Dutch) mutants. The association free energy of small beta-sheet oligomers shows near-linear trend with the dimers being thermodynamically more stable relative to the larger constructs. The linear (within statistical uncertainty) dependence of the association free energy on complex size is a consequence of the unilateral stacking of monomers in the beta-sheet oligomers. The charge reduction of the wild-type Abeta(17-42) oligomers upon protonation of the solvent-exposed Glu(22) at acidic conditions results in lowering the association free energy compared to the wild-type oligomers at neutral pH and the E22Q mutants. The neutralization of the peptides because of the E22Q mutation only marginally affects the association free energy, with the reduction of the direct electrostatic interactions mostly compensated by the unfavorable electrostatic solvation effects. For the wild-type oligomers at acidic conditions such compensation is not complete, and the electrostatic interactions, along with the gas-phase nonpolar energetic and the overall entropic effects, contribute to the lowering of the association free energy. The differences in the association thermodynamics between the wild-type Abeta(17-42) oligomers at neutral pH and the Dutch mutants, on the one hand, and the Abeta(17-42) oligomers with protonated Glu(22), on the other, may be explained by destabilization of the inter- and intrapeptide salt bridges between Asp(23) and Lys(28). Peculiarities in the conformational stability and the association thermodynamics for the different models of the Abeta(17-42) oligomers are rationalized based on the analysis of the local physical interactions and the microscopic solvation structure.

Dataset Information

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid ? Assemblies.

Publications

Conformational Dynamics and Stability of U-Shaped and S-Shaped Amyloid β Assemblies.

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