O-O bond splitting mechanism in cytochrome oxidase

Hybrid density functional theory (DFT) calculations have been used to inves tigate different mechanisms for O-O bond splitting in cytochrome oxidase. I t is shown that the requirement for a low activation barrier for the O-O bo nd splitting is that two protons, apart from the tyrosine hydroxyl proton, are available at the binuclear center. A mechanism is suggested for the tra nsformation from a species with a molecularly coordinated O-2, to an O-O cl eaved species with an oxo-ferryl group, The mechanism has a calculated acti vation barrier in reasonable agreement with experimental estimates, and the overall reaction is close to thermoneutral, in line with the requirement t hat the energy wasted as heat should be minimized. The rate limiting step i n the mechanism occurs at the initial Fe-O-2 intermediate, consistent with experimental observations that the decay of the oxy intermediate parallels the increase of the oxo product. The formation of a radical at the cross-li nked tyrosine-histidine structure is a possible source for one of the elect rons required in the bond cleavage process. Possible sources for the two pr otons are discussed, including a suggested key role for the hydroxyl group on the farnesyl side chain of heme a(3). (C) 2000 Elsevier Science S.A. All rights reserved.