Effects of Cu ions and explicit water molecules on the copper binding domain of amyloid precursor protein...

Amyloid precursor protein (APP) is a cell-surface trans-membrane glycoprotein that appears to play an important role in in vivo Cu ion homeostasis. This protein includes a copper-binding-domain (CuBD) fragment consisting of residues 124-189, of which His147, His151, Tyr168, and possibly Met170 comprise the explicit Cu-binding site (CuBS). Molecular dynamics (MD) simulations are carried out on Cu-free and Cu-bound APP models, based on crystal structures including residues 131-189 obtained from the Protein Data Bank, to confirm the site of Cu-ion binding and to elucidate the effects of the oxidation state of the Cu ions (default GROMACS parameters modeled only the electrostatic binding to the Cu ions at the CuBS) and explicit water molecules on the conformational properties of the 131-189 residue portion of the CuBD. MD trajectory analysis demonstrated a conformational change of Met170. The sulfur atom of Met170 moves closer to the Cu(II) ion and away from Cu(I), and this change may play an important role in the reduction of Cu(II) and the release of Cu(I). Two explicit water molecules were included in the MD simulations. These water molecules that bind strongly to the Cu ions via their lone pair electrons result in a significant modification of the binding interactions with the other residues at the CuBS.