A thermodynamic analysis using density functional theory suggests a parallelism between the mechanisms of cytochrome c oxidase and that of a bimetallic alloy catalyst for reducing oxygen to water. It is shown that ionic sites such as those in enzymes are thermodynamically more favorable than neutral atoms composing the alloy to catalyze specific reaction steps. The potential for designing novel effective oxygen reduction catalysts is discussed. (c) 2007 Elsevier B.V. All rights reserved.