Insights into Cu(I) exchange in HAH1 using quantum mechanical and molecular simulations

The human antioxidant protein, HAH1, is an important participant in a Cu(I) transport chain, delivering one Cu(I) ion to the Wilson's (WND) or Menkes disease protein (MNK). Full geometry optimizations and second-derivative calculations were performed on several binding site models using the B3LYP functional to derive parameters for the construction of a novel molecular mechanical (MM) force field for Cu(I) and its ligating residues in HAH1. MM minimization and molecular dynamics (MD) calculations were then performed using the AMBER suite to validate the newly generated force field. The X-ray crystal structure of the protein and the geometry of the Cu(I) binding site within the protein were reproduced by the MD simulations on the protein based on rmsd and visual inspection, validating the new force field parameters. The results from the quantum mechanical (QM) and MD simulations suggest that either a two- or three-coordinate exchange reaction is preferred and that it is unlikely that a four-coordinate Cu(I) species plays a role in copper exchange.