To maintain correct copper homeostasis,
the body relies on ion binding metallochaperones, cuprophilic ligands,
and proteins to move copper around as a complexed metal. The most
common binding site for Cu(I) proteins is the CX<sub>1</sub>X<sub>2</sub>C motif, where X<sub>1</sub> and X<sub>2</sub> are nonconserved
residues. Although this binding site motif is well established, the
mechanistic and electronic details for the transfer of Cu(I) between
two binding sites have not been fully established, in particular,
whether the transfer is dissociative or associative or if the electron-rich
Cu(I)–Cys interactions influence the transfer. In this work,
we investigated the electronic structure of the Cu(I)–S interactions
during the copper transfer between Atox1 and a metal binding domain
on the ATP7A or ATP7B protein. Initially, three Cu(I) methylthiolate
complexes, [Cu(SCH<sub>3</sub>)<sub>2</sub>]<sup>−1</sup>,
[Cu(SCH<sub>3</sub>)<sub>3</sub>]<sup>−2</sup>, [Cu(SCH<sub>3</sub>)<sub>4</sub>]<sup>−3</sup>, were investigated with
density functional theory (DFT) to fully elucidate the electronic
structure and bonding between Cu(I) and thiolate species. The two-coordinate,
linear species with a C–S–S–C dihedral angle
of ∼90° is the lowest energy conformation because the
filled π antibonding orbitals are stabilized in this geometry.
The importance of π-overlap is also seen with the trigonal planar,
three-coordinate Cu(I) complex, which is similarly stabilized. A corresponding
four-coordinate species could not be consistently optimized, so it
was concluded that tetrahedral coordination was not likely to be stable.
The transfer of Cu(I) from the Atox1 metallochaperone to a metal binding
domain of the ATP7A or ATP7B protein was then modeled by using the
CGGC Atox1 binding site for the donor model and the dithiotreitol
ligand (DTT) for the acceptor model. The two- and three-coordinate
intermediates calculated along the five-step transfer mechanism converged
to near optimal Cu–S π-overlap for the respective geometries,
which demonstrates that the electronic structure in this electron-rich
environment influences the intermediate’s geometries in the
transfer mechanism