title: Benchmarking of copper(II) LFMM parameters for studying amyloid-β peptides.
abstract: Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1-16peptide fragment. Several density functional theory (DFT) optimised small test models, representative of different possible copper coordination modes, have been used to test the accuracy of the LFMM copper bond lengths and angles, resulting in errors typically less than 0.1 Å and 5°. Ligand field molecular dynamics (LFMD) simulations have been carried out on the copper bound amyloid-β1-16peptide and snapshots extracted from the subsequent trajectory. Snapshots have been optimised using DFT and the semi-empirical PM7 method resulting in good agreement against the LFMM calculated geometry. Analysis of substructures within snapshots shows that the larger contribution of geometrical difference, as measured by RMSD, lies within the peptide backbone, arising from differences in DFT and AMBER, and the copper coordination sphere is reproduced well by LFMM. PM7 performs excellently against LFMM with an average RMSD of 0.2 Å over 21 tested snapshots. Further analysis of the LFMD trajectory shows that copper bond lengths and angles have only small deviations from average values, with the exception of a carbonyl moiety from the N-terminus, which can act as a weakly bound fifth ligand.
authors.affiliation: a School of Chemistry , Cardiff University , Park Place, Cardiff CF10 3AT , UK.
authors.forename: Shaun T
authors.initials: ST
authors.lastname: Mutter
authors.affiliation: b Department of Chemistry , University of Warwick , Gibbet Hill, Coventry CV4 7AL , UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Deeth
authors.affiliation: a School of Chemistry , Cardiff University , Park Place, Cardiff CF10 3AT , UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Turner
authors.affiliation: a School of Chemistry , Cardiff University , Park Place, Cardiff CF10 3AT , UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Platts
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D003300:Copper / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D003300:Copper
keywords: amyloid-beta peptide; copper; ligand field molecular mechanics; molecular dynamics