Atomistic Simulations Indicate Cardiolipin to have an Integral Role in the Structure of the Cytochrome bc1 Complex

Abstract

The reaction mechanism of the cytochrome bc1 (cyt bc1) complex relies on proton and electron transfers to/from substrate quinone/quinol, which in turn generates a proton gradient across the mitochondrial membrane used in the ATP synthesis. Cardiolipins (CLs) have been suggested to both ensure the structural integrity of the complex and take part in the proton uptake. We study the issue by simulating the entire cyt bc1 dimer of purple photosynthetic bacterium Rhodobacter capsulatus embedded into a lipid bilayer using all-atom molecular dynamics. In the 200 ns simulations CLs position themselves in the dimer interface and around the protein close to the higher potential heme groups of the enzyme complex's catalytic Qi-sites, in line with the positioning seen in the crystal structures. The arrangement of CLs close to the Qi-sites supports the proposed view of these highly charged phospholipids as key players in the proton uptake. Based on the simulations we also present a refined dimer arrangement for the cyt bc1 complex that encompasses the full effect of the surrounding lipid environment. The periplasmic domains of the complex spread against the membrane; moreover, this conformational shift was more pronounced when Qo-site lacked a bound substrate. As a whole, the applied modeling approach provides novel insights into the lipid-cyt bc1 dynamics, complementing the previous experimental findings.