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The unique Alzheimer's ?-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.

ABSTRACT: Elucidating the structure of A?(1-40) fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target A?(1-40) fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across ?-strands and across ?-sheets in A? fibrils. Experimentally, data for the three-fold symmetry structure of the A?(9-40) fibril suggest formation of tight hydrophobic core through M35 interactions across the fibril axis and strong I31-V39 interactions between different cross-? units. Herein, on the basis of experimental data, we probe conformers with three-fold symmetry of the full-length A?(1-40). Our all-atom molecular dynamics simulations in explicit solvent of conformers based on the ssNMR data reproduced experimental observations of M35-M35 and I31-V39 distances. Our interpretation of the experimental data suggests that the observed ?5-7 Å M35-M35 distance in the fibril three-fold symmetry structure is likely to relate to M35 interactions along the fibril axis, rather than across the fibril axis, since our measured M35-M35 distances across the fibril axis are consistently above 15 Å. Consequently, we revealed that the unique A?(1-40) triangular structure has a large cavity along the fibril axis and that the N-termini can assist in the stabilization of the fibril by interacting with the U-turn domains or with the C-termini domains. Our findings, together with the recent cyroEM characterization of the hollow core in A?(1-42) fibrils, point to the relevance of a cavity in A?(1-40/1-42) oligomers which should be considered when targeting oligomer toxicity.

SUBMITTER: Miller Y

PROVIDER: S-EPMC3045480 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The unique Alzheimer's β-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.

Miller Yifat Y Ma Buyong B Nussinov Ruth R

Journal of the American Chemical Society 20110207 8

Elucidating the structure of Aβ(1-40) fibrils is of interest in Alzheimer's disease research because it is required for designing therapeutics that target Aβ(1-40) fibril formation at an early stage of the disease. M35 is a crucial residue because of its potential oxidation and its strong interactions across β-strands and across β-sheets in Aβ fibrils. Experimentally, data for the three-fold symmetry structure of the Aβ(9-40) fibril suggest formation of tight hydrophobic core through M35 interac ...[more]

PMID: 21299220

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Project description:Nanoscale fibrils formed by amyloid peptides have a polymorphic character, adopting several types of molecular structures in similar growth conditions. As shown by experimental (e.g., solid-state NMR) and computational studies, amyloid fibril polymorphism hinders both the structural characterization of Alzheimer's Aβ amyloid protofilaments and fibrils at a molecular level, as well as the possible applications (e.g., development of drugs or biomarkers) that rely on similar, controlled molecular arrangements of the Aβ peptides in amyloid fibril structures. We have explored the use of several contact potentials for the efficient identification of minimal sequence mutations that could enhance the stability of specific fibril structures while simultaneously destabilizing competing topologies, controlling thus the amount of structural polymorphism in a rational way. We found that different types of contact potentials, while having only partial accuracy on their own, lead to similar results regarding ranking the compatibility of wild-type (WT) and mutated amyloid sequences with different fibril morphologies. This approach allows exhaustive screening and assessment of possible mutations and the identification of minimal consensus mutations that could stabilize fibrils with the desired topology at the expense of other topology types, a prediction that is further validated using atomistic molecular dynamics with explicit water molecules. We apply this two-step multiscale (i.e., residue and atomistic-level) approach to predict and validate mutations that could bias either parallel or antiparallel packing in the core Alzheimer's Aβ9-40 amyloid fibril models based on solid-state NMR experiments. Besides shedding new light on the molecular origins of structural polymorphism in WT Aβ fibrils, our study could also lead to efficient tools for assisting future experimental approaches for amyloid fibril determination, and for the development of biomarkers or drugs aimed at interfering with the stability of amyloid fibrils, as well as for the future design of amyloid fibrils with a controlled (e.g., reduced) level of structural polymorphism.

Dataset Information

The unique Alzheimer's ?-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.

Publications

The unique Alzheimer's β-amyloid triangular fibril has a cavity along the fibril axis under physiological conditions.

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