Understanding Kinase Activation of ALK in Neuroblastoma Patients

Abstract

The cytochrome bc 1 complex (bc 1 ) is a widespread, dimeric redox-driven proton translocase. It oxidizes molecules of ubiquinol (UQH2) in the site Q P of the cytochrome b subunit, whereby the two released electrons are transferred, respectively, to the heme of cytochrome c 1 -via the mobile soluble domain of the Rieske protein (the ''head'' domain) -and to a ubiquinone (UQ) molecule in the Q N 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 Q N site. Thermodynamics considerations also indicate that the ability of the Rieske ''head'' domain in one monomer to move towards cytochrome c 1 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 bc 1 dimer remain elusive.In the present study, large-scale MD simulations were used to track the communications within the bc 1 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 Q N site. Equilibrium and metadynamics simulations of the bc 1 revealed two distinct binding modes for semiquinone (SQ) and UQH2/UQ in the Q N site and the two positions of UQ in the Q P site which corresponded to these Q N modes, whereby a SQ in the Q N 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 bc 1 monomer could easier move towards cytochrome c 1 when the ''head'' domain in the opposite monomer was docked to cytochrome b.