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Quantum chemical molecular dynamics and metadynamics simulation of aluminium binding to amyloid-β and related peptides

Platts, James A. 2020. Quantum chemical molecular dynamics and metadynamics simulation of aluminium binding to amyloid-β and related peptides. Royal Society Open Science 7 (2) , 191562. 10.1098/rsos.191562

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Abstract

We report semi-empirical tight-binding simulations of the interaction between Al(III) and biologically relevant peptides. The GFN2-XTB method is shown to accurately reproduce previously reported and density functional theory (DFT)-calculated geometries of model systems. Molecular dynamics simulations based on this method are able to sample peptide flexibility over timescales of up to nanoseconds, but these timescales are insufficient to explore potential changes in metal–peptide binding modes. To achieve this, metadynamics simulations using root mean square deviation as a collective variable were employed. With suitably chosen biasing potentials, these are able to efficiently explore diverse coordination modes, for instance, through Glu and/or Asp residues in a model peptide. Using these methods, we find that Al(III) binding to the N-terminal sequence of amyloid-β is highly fluxional, with all acidic sidechains and several backbone oxygens participating in coordination. We also show that such simulations could provide a means to predict a priori possible binding modes as a precursor to longer, atomistic simulations.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Chemistry
Publisher: Royal Society, The
ISSN: 2054-5703
Funders: EPSRC
Date of First Compliant Deposit: 13 February 2020
Date of Acceptance: 10 December 2019
Last Modified: 17 Feb 2020 13:55
URI: http://orca.cf.ac.uk/id/eprint/129610

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