Inter- and Intra-Monomeric Communication in the Cytochrome Bc1 Complex: A Molecular Dynamics Study

Abstract

The cytochrome bc1 complex (bc1) is a widespread, dimeric redox-driven proton translocase. It oxidizes molecules of ubiquinol (UQH2) in the site QP of the cytochrome b subunit, whereby the two released electrons are transferred, respectively, to the heme of cytochrome c1 - via the mobile soluble domain of the Rieske protein (the “head” domain) - and to a ubiquinone (UQ) molecule in the QN site of cytochrome b.Earlier kinetic studies have indicated that the movement of the Rieske “head” domain could be coupled with the quinone reduction in the QN site. Thermodynamics considerations also indicate that the ability of the Rieske “head” domain in one monomer to move towards cytochrome c1 might be coupled with the docking of the “head” domain to cytochrome b in the other monomer. However, the details of such mechanistic coupling within the bc1 dimer remain elusive.In the present study, large-scale MD simulations were used to track the communications within the bc1 of Rhodobacter sphaeroides.Different computational techniques (correlation analysis of interaction energies, motion cross-correlation, co-evolution of amino acid positions) have revealed possible pathways for transmembrane propagation of information about the redox state of UQ in the QN site. Equilibrium and metadynamics simulations of the bc1 revealed two distinct binding modes for semiquinone (SQ) and UQH2/UQ in the QN site and the two positions of UQ in the QP site which corresponded to these QN modes, whereby a SQ in the QN site favored tighter docking of the Rieske “head” domain and hindered its outward motion. Metadynamics simulations also showed that the Rieske “head” domain of one bc1 monomer could easier move towards cytochrome c1 when the “head” domain in the opposite monomer was docked to cytochrome b.