Computational microscopy of the supramolecular organization of the respiratory chain complexes

This thesis addresses the association of the protein complexes of the respiratory chain into highly organized structures called supercomplexes (SC). More specifically, the thesis focuses on the involvement of the membrane in this association process, and the potential roles of one of its main lipidic components, cardiolipin (CL). The main hypothesis being CL would contribute to the stability of the respiratory chain assembly by “gluing” the complexes together.

Using the coarse grain molecular dynamics (CGMD) simulation technique, I investigated two main hypotheses: 1) if CLs are involved in stabilizing the association of the complexes into supercomplexes; 2) assuming the presence of CL binding sites, one can imagine two potential mechanisms of action: CL could act as locks or bridges. In both cases, unfavorable interactions between complexes are avoided by CL capping parts of the complex surfaces. The first hypothesis is developed in the Chapters III and IV of this thesis, for the respective complex III (CIII, cytochrome bc1 complex) and complex IV (CIV, cytochrome c oxidase) of the respiratory chain. The second hypothesis was then assessed by looking at the self-assembly of the two complexes and is presented in Chapter V. In an effort to further increase the speed of CGMD simulations, I developed a new model presented in Chapter VI. The number of degrees of freedom of the system was reduced by removing the aqueous phase, which usually represents a significant part of a simulation box.