Anionic Lipids Confine Cytochrome c 2 to the Surface of Bioenergetic Membranes without Compromising Its Interaction with Redox Partners.

Cytochrome c 2 (cyt. c 2 ) is a major element in electron transfer between redox proteins in bioenergetic membranes. While the interaction between cyt. c 2 and anionic lipids abundant in bioenergetic membranes has been reported, their effect on the shuttling activity of cyt. c 2 remains elusive. Here, the effect of anionic lipids on the interaction and binding of cyt. c 2 to the cytochrome bc 1 complex ( bc 1 ) is investigated using a combination of molecular dynamics (MD) and Brownian dynamics (BD) simulations. MD is used to generate thermally accessible conformations of cyt. c 2 and membrane-embedded bc 1 , which were subsequently used in multireplica BD simulations of diffusion of cyt. c 2 from solution to bc 1 , in the presence of various lipids. We show that, counterintuitively, anionic lipids facilitate association of cyt. c 2 with bc 1 by localizing its diffusion to the membrane surface. The observed lipid-mediated bc 1 association is further enhanced by the oxidized state of cyt. c 2 , in line with its physiological function. This lipid-mediated enhancement is salinity-dependent, and anionic lipids can disrupt cyt. c 2 - bc 1 interaction at nonphysiological salt levels. Our data highlight the importance of the redox state of cyt. c 2 , the lipid composition of the chromatophore membrane, and the salinity of the chromatophore in regulating the efficiency of the electron shuttling process mediated by cyt. c 2 . The conclusions can be extrapolated to mitochondrial systems and processes, or any bioenergetic membrane, given the structural similarity between cyt. c 2 and bc 1 and their mitochondrial counterparts.