A theoretical investigation of the functional role of the axial methionine ligand of the CuA site in cytochrome c oxidase

The functional roles of the amino acid residues of the CuA site in bovine cytochrome c oxidase (CcO) were investigated by utilizing hybrid quantum mechanics (QM)/molecular mechanics (MM) calculations. The energy levels of the molecular orbitals (MOs) involving Cu dzx orbitals unexpectedly increased, as compared with those found previously with a simplified model system lacking the axial Met residue (i.e., Cu2S2N2). This elevation of MO energies stemmed from the formation of the anti-bonding orbitals, which are generated by hybridization between the dzx orbitals of Cu ions and the p-orbitals of the S and O atoms of the axial ligands. To clarify the roles of the axial Met ligand, the inner-sphere reorganization energies of the CuA site were computed, with the Met residue assigned to either the QM or MM region. The reorganization energy slightly increased when the Met residue was excluded from the QM region. The existing experimental data and the present structural modeling study also suggested that the axial Met residue moderately increased the redox potential of the CuA site. Thus, the role of the Met may be to regulate the electron transfer rate through the fine modulation of the electronic structure of the CuA “platform”, created by two Cys/His residues coordinated to the Cu ions. This regulation would provide the optimum redox potential/reorganization energy of the CuA site, and thereby facilitate the subsequent cooperative reactions, such as the proton pump and the enzymatic activity, of CcO. This article is part of a Special Issue entitled: Allosteric cooperativity in respiratory proteins.

Figure optionsDownload high-quality image (170 K)Download as PowerPoint slideHighlights
► Theoretical study of the CuA site of bovine cytochrome c oxidase.
► Fine-modulation of the electronic state of the CuA “platform” by the axial Met.
► CuA established by this modulation triggers the subsequent cooperative reactions.