Clarifying the Roles of Cardiolipin

Abstract

Cardiolipins (CL) are uniquely structured double lipids that are universally found in membranes which couple electron transport and phosphorylation. The proposed roles of CL in these membranes include mainly two aspects: the effects on the structure and dynamics of the membranes' lipid component and the interplay with membrane-associated proteins. In previous work, we have studied both of these aspects by utilizing atomistic molecular dynamics simulations, starting with the general effects of CL on membrane properties and the interplay with ions [1], further moving on to the interactions with the membrane-embedded respiratory complex cyt bc1 [2]. The latter model system that is of greater interest comprises the entire cyt bc1 dimer of the purple photosynthetic bacterium Rhodobacter capsulatus embedded in a lipid bilayer, whose lipid composition mimics that of the inner mitochondrial membrane. Intriguingly CLs were observed to diffuse spontaneously to the dimer interface and to the immediate vicinity of the catalytic Qi-sites [2]. This observation is in agreement with experimental data, as CLs are indeed located close to the Qi-sites in several X-ray crystal structures of the complex. Importantly, our observations support the proposed role of CL in delivering protons for the non-reduced substrate forms in the active site.In ongoing work that we discuss here we focus more specifically on the roles of individual components of the proposed proton uptake pathway (CL, water, and individual protein residues) and on the atom-level reaction mechanism in the binding pocket. To this end, further MD simulations, QM calculations, and cite-directed mutagenesis experiments were employed. We also discuss whether there is a plausible pathway for substrate movement between the active sites through the lipid-filled insides of the complex, and the role of oxidative stress in cyt bc1 behavior.