Abstract
Ligand field molecular mechanics (LFMM) parameters have been benchmarked for copper (II) bound to the amyloid-β1–16 peptide 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-β1–16 peptide 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.
Highlights
Alzheimer’s disease is one of the major health challenges facing modern society
Parameters were refined against density functional theory (DFT) structures of model complexes, tested for Cu(II)–Aβ1–16 and smaller models representative of the metal binding within this system
Ligand field molecular mechanics (LFMM) parameters were initially tested against DFT results on six simple four-coordinate copper complexes
Summary
Alzheimer’s disease is one of the major health challenges facing modern society. The N-terminus of Aβ contains several residues that can act as ligands towards transition metals, (Bolognin et al, 2011; Kowalik-Jankowska, Ruta-Dolejsz, Wisniewska, & Lankiewicz, 2001; Zirah et al, 2006) such that the structural and/or chemical effects of metal coordination have been proposed to play a role in the onset of Alzheimer’s (Bush, 2003; Spinello, Bonsignore, Barone, Keppler, & Terenzi, 2016). Non-natural metals such as platinum show promise as potential anti-Alzheimer’s agents through disruption of native metal coordination (Barnham et al, 2008; Turner, Platts, & Deeth, 2016).
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have