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Structural basis for A?1–42 toxicity inhibition by A? C-terminal fragments: discrete molecular dynamics study.

ABSTRACT: Amyloid ?-protein (A?) is central to the pathology of Alzheimer's disease. Of the two predominant A? alloforms, A?(1-40) and A?(1-42), the latter forms more toxic oligomers. C-terminal fragments (CTFs) of A? were recently shown to inhibit A?(1-42) toxicity in vitro. Here, we studied A?(1-42) assembly in the presence of three effective CTF inhibitors and an ineffective fragment, A?(21-30). Using a discrete molecular dynamics approach that recently was shown to capture key differences between A?(1-40) and A?(1-42) oligomerization, we compared A?(1-42) oligomer formation in the absence and presence of CTFs or A?(21-30) and identified structural elements of A?(1-42) that correlated with A?(1-42) toxicity. CTFs co-assembled with A?(1-42) into large heterooligomers containing multiple A?(1-42) and inhibitor fragments. In contrast, A?(21-30) co-assembled with A?(1-42) into heterooligomers containing mostly a single A?(1-42) and multiple A?(21-30) fragments. The CTFs, but not A?(21-30), decreased the ?-strand propensity of A?(1-42) in a concentration-dependent manner. CTFs and A?(21-30) had a high binding propensity to the hydrophobic regions of A?(1-42), but only CTFs were found to bind the A?(1-42) region A2-F4. Consequently, only CTFs but not A?(21-30) reduced the solvent accessibility of A?(1-42) in region D1-R5. The reduced solvent accessibility of A?(1-42) in the presence of CTFs was comparable to the solvent accessibility of A?(1-40) oligomers formed in the absence of A? fragments. These findings suggest that region D1-R5, which was more exposed to the solvent in A?(1-42) than in A?(1-40) oligomers, is involved in mediating A?(1-42) oligomer neurotoxicity.

SUBMITTER: Urbanc B

PROVIDER: S-EPMC3124842 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Structural basis for Aβ1–42 toxicity inhibition by Aβ C-terminal fragments: discrete molecular dynamics study.

Urbanc B B Betnel M M Cruz L L Li H H Fradinger E A EA Monien B H BH Bitan G G

Journal of molecular biology 20110523 2

Amyloid β-protein (Aβ) is central to the pathology of Alzheimer's disease. Of the two predominant Aβ alloforms, Aβ(1-40) and Aβ(1-42), the latter forms more toxic oligomers. C-terminal fragments (CTFs) of Aβ were recently shown to inhibit Aβ(1-42) toxicity in vitro. Here, we studied Aβ(1-42) assembly in the presence of three effective CTF inhibitors and an ineffective fragment, Aβ(21-30). Using a discrete molecular dynamics approach that recently was shown to capture key differences between Aβ(1 ...[more]

PMID: 21621545

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Project description:The knowledge of multiple conformational states is a prerequisite to understand the function of membrane transport proteins. Unfortunately, the determination of detailed atomic structures for all these functionally important conformational states with conventional high-resolution approaches is often difficult and unsuccessful. In some cases, biophysical and biochemical approaches can provide important complementary structural information that can be exploited with the help of advanced computational methods to derive structural models of specific conformational states. In particular, functional and spectroscopic measurements in combination with site-directed mutations constitute one important source of information to obtain these mixed-resolution structural models. A very common problem with this strategy, however, is the difficulty to simultaneously integrate all the information from multiple independent experiments involving different mutations or chemical labels to derive a unique structural model consistent with the data. To resolve this issue, a novel restrained molecular dynamics structural refinement method is developed to simultaneously incorporate multiple experimentally determined constraints (e.g., engineered metal bridges or spin-labels), each treated as an individual molecular fragment with all atomic details. The internal structure of each of the molecular fragments is treated realistically, while there is no interaction between different molecular fragments to avoid unphysical steric clashes. The information from all the molecular fragments is exploited simultaneously to constrain the backbone to refine a three-dimensional model of the conformational state of the protein. The method is illustrated by refining the structure of the voltage-sensing domain (VSD) of the Kv1.2 potassium channel in the resting state and by exploring the distance histograms between spin-labels attached to T4 lysozyme. The resulting VSD structures are in good agreement with the consensus model of the resting state VSD and the spin-spin distance histograms from ESR/DEER experiments on T4 lysozyme are accurately reproduced.

Dataset Information

Structural basis for A?1–42 toxicity inhibition by A? C-terminal fragments: discrete molecular dynamics study.

Publications

Structural basis for Aβ1–42 toxicity inhibition by Aβ C-terminal fragments: discrete molecular dynamics study.

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