Respiratory Complex III: A Bioengine with a Ligand-Triggered Electron-Tunneling Gating Mechanism

Respiratory complex III (a.k.a., the bc₁ complex) plays a key role in the electron transport chain in aerobic cells. The bc₁ complex exhibits multiple unique electron tunneling (ET) processes, such as ET-bifurcation at the Q_o site and movement of the Rieske domain. Moreover, we previously discovered that electron tunneling in the low potential arm of the bc₁ complex is regulated by a key phenylalanine residue (Phe90). The main goal of the current work is to study the dynamics of the key Phe90 residue in the electron tunneling reaction between heme b_L and heme b_H as a function of the occupancy of the Q_o and Q_i binding sites in the bc₁ complex. We simulated the molecular dynamics of four model systems of respiratory complex III with different ligands bound at the Q_o and Q_i binding sites. In addition, we calculated the electron tunneling rate constants between heme b_L and heme b_H along the simulated molecular dynamics trajectories. The binding of aromatic ligands at the Q_o site induces a conformational cascade that properly positions the Phe90 residue, reducing the through-space ET distance from ∼7 to ∼5.5 Å and thus enhancing the electron transfer rate between the heme b_L and the heme b_H redox pair. Also, the binding of aromatic ligands at the Q_i site induces conformational changes that stabilize the Phe90 conformational variation from ∼1.5 to ∼0.5 Å. Hence, our molecular dynamics simulation results show an on-demand two-step conformational connection between the occupancy of the Q_o and Q_i binding sites and the conformational dynamics of the Phe90 residue. Additionally, our dynamic electron tunneling results confirm our previously reported findings that the Phe90 residue acts as an electron-tunneling gate or switch, controlling the electron transfer rate between the heme b_L and heme b_H redox systems.