Dataset Information

Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.

ABSTRACT: The aggregation of amyloid beta (A?) peptides plays an important role in the development of Alzheimer's disease. Despite extensive effort, it has been difficult to characterize the secondary and tertiary structure of the A? monomer, the starting point for aggregation, due to its hydrophobicity and high aggregation propensity. Here, we employ extensive molecular dynamics simulations with atomistic protein and water models to determine structural ensembles for A?(42), A?(40), and A?(42)-E22K (the Italian mutant) monomers in solution. Sampling of a total of >700 microseconds in all-atom detail with explicit solvent enables us to observe the effects of peptide length and a pathogenic mutation on the disordered A? monomer structural ensemble. A?(42) and A?(40) have crudely similar characteristics but reducing the peptide length from 42 to 40 residues reduces ?-hairpin formation near the C-terminus. The pathogenic Italian E22K mutation induces helix formation in the region of residues 20-24. This structural alteration may increase helix-helix interactions between monomers, resulting in altered mechanism and kinetics of A? oligomerization.

SUBMITTER: Lin YS

PROVIDER: S-EPMC3260686 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.

Lin Yu-Shan YS Bowman Gregory R GR Beauchamp Kyle A KA Pande Vijay S VS

Biophysical journal 20120101 2

The aggregation of amyloid beta (Aβ) peptides plays an important role in the development of Alzheimer's disease. Despite extensive effort, it has been difficult to characterize the secondary and tertiary structure of the Aβ monomer, the starting point for aggregation, due to its hydrophobicity and high aggregation propensity. Here, we employ extensive molecular dynamics simulations with atomistic protein and water models to determine structural ensembles for Aβ(42), Aβ(40), and Aβ(42)-E22K (the ...[more]

PMID: 22339868

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Project description:α-Synuclein is an intrinsically disordered protein occurring in different conformations and prone to aggregate in β-sheet structures, which are the hallmark of the Parkinson disease. Missense mutations are associated with familial forms of this neuropathy. How these single amino-acid substitutions modify the conformations of wild-type α-synuclein is unclear. Here, using coarse-grained molecular dynamics simulations, we sampled the conformational space of the wild type and mutants (A30P, A53P, and E46K) of α-synuclein monomers for an effective time scale of 29.7 ms. To characterize the structures, we developed an algorithm, CUTABI (CUrvature and Torsion based of Alpha-helix and Beta-sheet Identification), to identify residues in the α-helix and β-sheet from Cα -coordinates. CUTABI was built from the results of the analysis of 14,652 selected protein structures using the Dictionary of Secondary Structure of Proteins (DSSP) algorithm. DSSP results are reproduced with 93% of success for 10 times lower computational cost. A two-dimensional probability density map of α-synuclein as a function of the number of residues in the α-helix and β-sheet is computed for wild-type and mutated proteins from molecular dynamics trajectories. The density of conformational states reveals a two-phase characteristic with a homogeneous phase (state B, β-sheets) and a heterogeneous phase (state HB, mixture of α-helices and β-sheets). The B state represents 40% of the conformations for the wild-type, A30P, and E46K and only 25% for A53T. The density of conformational states of the B state for A53T and A30P mutants differs from the wild-type one. In addition, the mutant A53T has a larger propensity to form helices than the others. These findings indicate that the equilibrium between the different conformations of the α-synuclein monomer is modified by the missense mutations in a subtle way. The α-helix and β-sheet contents are promising order parameters for intrinsically disordered proteins, whereas other structural properties such as average gyration radius, R g , or probability distribution of R g cannot discriminate significantly the conformational ensembles of the wild type and mutants. When separated in states B and HB, the distributions of R g are more significantly different, indicating that global structural parameters alone are insufficient to characterize the conformational ensembles of the α-synuclein monomer.

Dataset Information

Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.

Publications

Investigating how peptide length and a pathogenic mutation modify the structural ensemble of amyloid beta monomer.

Similar Datasets

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