How does antimycin inhibit the bc1 complex? A part-time twin

Using a stochastic simulation without any other hypotheses, we recently demonstrated the natural emergence of the modified Mitchell Q-cycle in the functioning of the bc1 complex, with few short-circuits and a very low residence time of the reactive semiquinone species in the Qo site. However, this simple model fails to explain both the inhibition by antimycin of the bc1 complex and the accompanying increase in ROS production. To obtain inhibition, we show that it is necessary to block the return of the electron from the reduced haem bL to Qo. With this added hypothesis we obtain a sigmoid inhibition curve due to the fact that when only one antimycin is bound per bc1 dimer, the electron of the inhibited monomer systematically crosses the dimer interface from bL to bL to reduce a quinone or a semiquinone species in the other (free) Qi site. Because this step is not limiting, the activity is unchanged (compared to the activity of the free dimer). Interestingly, this bL–bL pathway is almost exclusively taken in this half-bound antimycin dimer. In the free dimer, the natural faster pathway is bL–bH on the same monomer. The addition of the assumption of half-of-the-sites reactivity to the previous hypothesis leads to a transient activation in the antimycin titration curve preceding a quasi-complete inhibition at antimycin saturation.