Probing the Effect of Cardiolipin on the Redox-Partner Recognition between Cytochrome C2 and Cytochrome Bc1 Complex

Abstract

Cytochrome c (cyt. c) and cytochrome bc1 (bc1) complex are redox proteins that participate in the electron transport chain of the mitochondria, with cyt. c shuttling electrons from bc1 complex to complex IV. Cyt. c and bc1 complex reside in the inner membrane of the mitochondria, which is rich in the negatively-charged cardiolipin (CL). CL concentration in mitochondria varies upon different physiological conditions, and in some cases, a depletion of CL leads to a reduced bc1 complex activity. In this study, the redox-partner recognition between cyt. c and bc1 complex is examined using molecular dynamic (MD) and Brownian dynamics (BD) simulations with variations in CL concentration and salinity. First, MD simulations were performed to equilibrate cyt c2 and bc1 complex with membranes of different CL concentrations to obtain atomistic representations of their in situ configurations. Then, for each CL concentration, the electrostatic potential profile as well as hydrophobic interactions under different salinities were determined; to serve as input parameters for BD simulations. Then, for each redox state of cyt. c2 and that of bc1 complex, as well as for each of the above-mentioned CL concentration, a set of 10 independent 200 microsecond BD simulations were performed to sample the binding likelihood between the two proteins. Our result shows that a match between the redox state of cyt. c2 and that of bc1 complex promotes the binding of the two proteins in all different conditions. However, the ability of cyt. c2 to distinguish bc1 complex from the membrane surface is susceptible to the corresponding electrostatic potential profile, which can be significantly modified by variations in CL concentration and salinity.