Molecular Dynamics Simulations of the Elusive Matrix-Open State of Mitochondrial ADP/ATP Carrier

We studied and compared in detail an elusive matrix open (m-state) and cytoplasmic open (c-state) state of ADP/ATP carrier (AAC) protein embedded in the DOPC bilayer by microsecond molecular dynamics (MD) simulations. We analyzed both states with and without cardiolipin (CDL) molecules, with a special emphasis on the recently obtained crystallographic structure of the AAC m-state. The obtained results show that both states of the protein are stable in the DOPC bilayer and impermeable to water. In comparison with the c-state of AAC, the m-state is more dynamic, but at the same time possesses a larger occluded area in the protein cavity. Both states of the protein are less flexible in simulations when CDL molecules are present, which is especially visible for the m-state. Finally, the analysis of the protein conformational changes during MD simulations shows that protein parts at the protein/lipid boundaries are prone to larger conformational changes in contrast to central region of the protein embedded in the bilayer core, thus further supporting the cycling mechanism suggested for ADP/ATP exchange by AAC.