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Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.

ABSTRACT: Elucidating the structural features of the Abeta monomer, the peptide constituent of amyloid fibrils found in Alzheimer's disease, can enable a direct characterization of aggregation pathways. Recent studies support the view that the ensemble of Abeta42 monomers is a mixture of diverse ordered and disordered conformational species, which can be classified according to the formation of a characteristic beta-hairpin conformation in a certain region. Despite the disparity in the structural features of these species, commonly used spectroscopic techniques such as NMR may not directly trace the conformational dynamics in the ensemble due to the limited time resolution and the lack of well-resolved spectral features for different comformers. Here we use molecular dynamics simulations combined with simulations of two-dimensional IR (2DIR) spectra to investigate the structure of these species, their interchange kinetics, and their spectral features. We show that while the discrimination efficiency of the ordinary, nonchiral 2DIR signal is limited due to its intrinsic dependence on common order parameters that are dominated by the generally unstructured part of the sequence, signals with carefully designed chirality-sensitive pulse configurations have the high resolution required for differentiating the various monomer structures. Our combined simulation studies indicate the power of the chirality-induced (CI) 2DIR technique in investigating early events in Abeta42 aggregation and open the possibility for their use as a novel experimental tool.

SUBMITTER: Zhuang W

PROVIDER: S-EPMC2936593 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.

Zhuang Wei W Sgourakis Nikolaos G NG Li Zhenyu Z Garcia Angel E AE Mukamel Shaul S

Proceedings of the National Academy of Sciences of the United States of America 20100823 36

Elucidating the structural features of the Abeta monomer, the peptide constituent of amyloid fibrils found in Alzheimer's disease, can enable a direct characterization of aggregation pathways. Recent studies support the view that the ensemble of Abeta42 monomers is a mixture of diverse ordered and disordered conformational species, which can be classified according to the formation of a characteristic beta-hairpin conformation in a certain region. Despite the disparity in the structural features ...[more]

PMID: 20798063

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Project description:As an important neuropathological hallmark of Alzheimer's disease (AD), the oligomerization of amyloid-β (Aβ) peptides has been intensively investigated in both theoretical and experimental studies. However, the oligomerization space in terms of the kinetics, molecular mechanism, and oligomer structures remains mysterious to us. An equation that can quantitatively describe the time it takes for Aβ oligomers to appear in the human brain at a given Aβ monomer concentration is extremely vital for us to understand the development and disease progression of AD. In this study, we utilized molecular dynamics (MD) simulations to investigate the oligomerization of Aβ42 peptides at five different monomer concentrations. We have elucidated the formation pathways of Aβ tetramers, characterized the oligomer structures, estimated the oligomerization time for Aβ dimers, trimers, and tetramers, and for the first-time derived equations that could quantitatively describe the relationship between the oligomerization time and the monomer concentration. Applying these equations, our prediction of oligomerization time agrees well with the experimental and clinical findings, in spite of the limitations of our oligomerization simulations. We have found that the Aβ oligomerization time depends on the monomer concentration by a power of -2.4. The newly established equations will enable us to quantitatively estimate the risk score of AD, which is a function of age. Moreover, we have identified the most dominant pathway of forming Aβ tetramers, probably the most important and toxic Aβ oligomer. Our results have shown that the structures of Aβ42 dimer, trimer, and tetramer, which are distinguishable from each other, depend on the monomer concentration at which the oligomers form. Representative oligomer structures, which can serve as potential drug targets, have been identified by clustering analysis. The MD sampling adequacy has been validated by the excellent agreement between the calculated and measured collisional cross section (CCS) parameters (the prediction errors are within 2%). In a conclusion, this study provides the kinetics and structure basis for developing inhibitors to decelerate the Aβ oligomerization process.

Dataset Information

Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.

Publications

Discriminating early stage A{beta}42 monomer structures using chirality-induced 2DIR spectroscopy in a simulation study.

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