Restricted Surface Diffusion of Cytochromes on Bioenergetic Membranes with Anionic Lipids

Bioenergetic membranes of mitochondria, thylakoids, and chromatophores are primary sites of ATP production in living cells. These membranes contain an electron transport chain (ETC) in which electrons are shuttled between a series of redox proteins during the generation of ATP via oxidative phosphorylation. The phospholipid composition of these membranes, which often include negative lipids, plays a role in determining the electrostatics of their surface owing to the spatial distribution of their charged head groups. Cardiolipin (CDL) is a phospholipid commonly associated with bioenergetic membranes and is also a significant contributor to the negative surface charge. Interactions between cytochromes and phospholipid head groups in the membrane can in principle affect the rate of its travel between ETC components, hence influencing the rate of ATP turnover. Here, we use molecular dynamic (MD) simulations that feature an accelerated membrane model, termed highly mobile membrane mimetic (HMMM), to study protein-lipid interactions during the diffusion of cytochrome <i>c</i>₂ between redox partners in a bioenergetic membrane. We observe a "skipping" mode of diffusion for cytochromes along with a bias for binding to anionic lipids, particularly with a strong preference for CDL. During diffusion, cytochrome <i>c</i>₂ maintains a relatively fixed tilt with respect to the membrane normal with wider fluctuations in its angle with respect to the plane of the membrane. The obtained results describing the behavior of cytochrome <i>c</i>₂ on a representative bioenergetic membrane have direct ramifications in shuttling motions of other similar electron-carrying elements in other bioenergetic membranes, which are composed of a significant amount of anionic lipids. The mode of surface-restricted diffusion reported here would modulate rapid electron transfer between the ETC complexes anchored in bioenergetic membranes by reducing the search space between them.