Molecular dynamics simulations of copper binding to N-terminus mutants of amyloid-β

We report results of molecular dynamic (MD) simulations on N-terminus mutants of the copper-bound, amyloid-β (Aβ) peptide. Eight structures of Aβ were modelled, including seven mutant peptides in addition to the unaltered wild-type (WT). Trajectories analysed for each individual system were all approximately 1.4 μs in length, yielding a total of over 11 μs in total. The impact of these mutations are marked and varied compared to the wild-type peptide, including effects on secondary structure, stability and conformational changes. Each system showed differing levels of stability with some showing consistent, compact conformations whereas others displayed more flexible structures. Contrasts between comparable mutations at similar sites, such as A2T/A2V and D7H/D7N, show the location as well as the type of mutation have effects on protein structure observed in Ramachandran plots. We also report notable changes in peptide structure at residues remote to the site of substitution showing these mutations influence the entirety of Aβ. Salt-bridge profiles show this most clearly: addition or removal of charged residues affecting all salt-bridge interactions present in WT, even those remote from the site of mutation. Effects on secondary structure differ between mutations, most notably a change in incidence of β-strand, which has been linked to enhanced aggregational properties for the peptide. GFN2-xTB semi-empirical calculations show clear differences in binding energies of the copper-centre for each system.Communicated by Ramaswamy H. Sarma.