Mutations in the D-channel of cytochrome c oxidase causes leakage of the proton pump

•Mutation effects at the entry of the D-channel of cytochrome oxidase.•Local effects at the entry point explain the experiments.•Energies of two points determine the rate of proton transfer.

It has experimentally been found that certain mutations close to the entry point of the proton transfer channel in cytochrome c oxidase stop proton translocation but not the oxygen reduction chemistry. This effect is termed uncoupling. Since the mutations are 20 Å away from the catalytic center, this is very surprising. A new explanation for this phenomenon is suggested here, involving a local effect at the entry point of the proton channel, rather than the long range effects suggested earlier.