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Elucidating the 3D structures of Al(iii)-A? complexes: a template free strategy based on the pre-organization hypothesis.

ABSTRACT: Senile plaques are extracellular deposits found in patients with Alzheimer's Disease (AD) and are mainly formed by insoluble fibrils of ?-amyloid (A?) peptides. The mechanistic details about how AD develops are not fully understood yet, but metals such as Cu, Zn, or Fe are proposed to have a non-innocent role. Many studies have also linked the non biological metal aluminum with AD, a species whose concentration in the environment and food has been constantly increasing since the industrial revolution. Gaining a molecular picture of how Al(iii) interacts with an A? peptide is of fundamental interest to improve understanding of the many variables in the evolution of AD. So far, no consensus has been reached on how this metal interacts with A?, partially due to the experimental complexity of detecting and quantifying the resulting Al(iii)-A? complexes. Computational chemistry arises as a powerful alternative to investigate how Al(iii) can interact with A? peptides, as suitable strategies could shed light on the metal-peptide description at the molecular level. However, the absence of any reliable template that could be used for the modeling of the metallopeptide structure makes computational insight extremely difficult. Here, we present a novel strategy to generate accurate 3D models of the Al(iii)-A? complexes, which still circumvents first principles simulations of metal binding to peptides of A?. The key to this approach lies in the identification of experimental structures of the isolated peptide that are favourably pre-organized for the binding of a given metal in configurations of the first coordination sphere that were previously identified as the most stable with amino acid models. This approach solves the problem of the absence of clear structural templates for novel metallopeptide constructs. The posterior refinement of the structures via QM/MM and MD calculations allows us to provide, for the first time, physically sound models for Al(iii)-A? complexes with a 1?:?1 stoichiometry, where up to three carboxylic groups are involved in the metal binding, with a clear preference towards Glu3, Asp7, and Glu11.

SUBMITTER: Mujika JI

PROVIDER: S-EPMC5613242 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Elucidating the 3D structures of Al(iii)-Aβ complexes: a template free strategy based on the pre-organization hypothesis.

Mujika Jon I JI Rodríguez-Guerra Pedregal Jaime J Lopez Xabier X Ugalde Jesus M JM Rodríguez-Santiago Luis L Sodupe Mariona M Maréchal Jean-Didier JD

Chemical science 20170509 7

Senile plaques are extracellular deposits found in patients with Alzheimer's Disease (AD) and are mainly formed by insoluble fibrils of β-amyloid (Aβ) peptides. The mechanistic details about how AD develops are not fully understood yet, but metals such as Cu, Zn, or Fe are proposed to have a non-innocent role. Many studies have also linked the non biological metal aluminum with AD, a species whose concentration in the environment and food has been constantly increasing since the industrial revol ...[more]

PMID: 28970891

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Project description:Chemical cross-linking is a powerful strategy for elucidating the structures of protein or protein complexes. The distance constraints obtained from cross-linked peptides represent the three-dimensional structures of the protein complexes. Unfortunately, structural analysis using cross-linking approach demands a significant amount of data to elucidate protein structures. This requires the development of several cleavable cross-linkers with different range of spacer chains. An Electron Transfer Dissociation (ETD) tandem mass spectrometry cleavable bond hydrazone was reported. Its fragmentation with conjugated peptides showed promise for the development of a new ETD cleavable cross-linker. However, no cross-linker was developed utilizing this ETD cleavable bond. For the first time, we attempted to develop an ETD cleavable cross-linker utilizing a hydrazone bond. We overcome the pitfall for the synthesis of this cross-linker and an easy synthesis scheme is reported. In this report, we evaluated the performance of this cross-linker called Hydrazone Incorporated ETD cleavable cross-linker (HI-ETD-XL) in model peptides and proteins. The characteristic fragmentation behavior of HI-ETD-XL during electron transfer dissociation and subsequent sequence identification of the peptide fragment ions by tandem mass spectrometry allowed the identification of cross-linked peptides unambiguously. We believe the availability of this ETD cleavable cross-linker will advance structural proteomics research significantly. SIGNIFICANCE: Many cellular processes rely on the structural dynamics of protein complexes. The detailed knowledge of the structure and dynamics of protein complexes is crucial for understanding their biological functions and regulations. However, most of the structure of these multiprotein entities remain uncharacterized and sometimes is very challenging to reveal with biophysical techniques alone. Chemical cross-linking combined with mass spectrometry (MS) has proven to be a dependable strategy in structural proteomics field. However, data complexity and false identifications are significant hindrances for unambiguous identification of cross-linked peptides. Confident identifications demand structural studies with cross-linkers with different properties and variable spacer chain lengths. This new ETD cleavable cross-linking workflow will provide additional confidence to overcome these drawbacks and allow us to pinpoint cross-linked peptides confidently.

Dataset Information

Elucidating the 3D structures of Al(iii)-A? complexes: a template free strategy based on the pre-organization hypothesis.

Publications

Elucidating the 3D structures of Al(iii)-Aβ complexes: a template free strategy based on the pre-organization hypothesis.

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