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Metal binding to amyloid β1-42: a ligand field molecular dynamics study

Mutter, Shaun, Turner, Matthew, Deeth, Robert J. and Platts, James A. 2018. Metal binding to amyloid β1-42: a ligand field molecular dynamics study. ACS Chemical Neuroscience 9 (11) , pp. 2795-2806. 10.1021/acschemneuro.8b00210

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Abstract

Ligand field molecular mechanics simulation has been used to model the interactions of copper(II) and platinum(II) with the amyloid-β1-42 peptide monomer. Molecular dynamics over several microseconds for both metallated systems are compared to analogous results for the free peptide. Significant differences in structural parameters are observed, both between Cu and Pt bound systems, as well as between free and metal-bound peptide. Both metals stabilise the formation of helices in the peptide as well as reducing the content of β secondary structural elements compared to the unbound monomer. This is in agreement with experimental reports of metals reducing β-sheet structures, leading to formation of amorphous aggregates over amyloid fibrils. The shape and size of the peptide structures also undergoes noteworthy change, with the free peptide exhibiting globular like structure, platinum(II) system adopting extended structures, and copper(II) system resulting in a mixture of conformations similar to both of these. Salt bridge networks exhibit major differences: the Asp23-Lys28 salt bridge, known to be important in fibril formation, has a differing distance profile within all three systems studied. Salt bridges in the metal binding region of the peptide are strongly altered, in particular the Arg5-Asp7 salt bridge, which has an occurrence of 71% in the free peptide, is reduced to zero in the presence of both metals.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Advanced Research Computing @ Cardiff (ARCCA)
Chemistry
Publisher: American Chemical Society
ISSN: 1948-7193
Funders: EP/N016858/1
Date of First Compliant Deposit: 18 June 2018
Date of Acceptance: 13 June 2018
Last Modified: 06 Feb 2020 15:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/112524

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