The Cu-A site is the electron mediator in cytochrome c oxidase (CcO), providing an appropriate electronic structure for rapid electron transfer. We have studied the coordinating effects of His, Met, and the peptide carbonyl group of Glu of the Cu-A site, using the density functional theory. Our computation demonstrates that the His ligation provides strong orbital and electrostatic effects on the electronic structure of the Cu-A site, while that the Met coordination gives weak orbital and electrostatic effects. A coordination of the peptide carbonyl group affects the electronic structure of the Cu-A site only electrostatically. (C) 2012 Elsevier B.V. All rights reserved.