Lipid loving ANTs: Molecular simulations of cardiolipin interactions and the organization of the adenine nucleotide translocase in model mitochondrial membranes

Journal article

The exchange of ADP and ATP across the inner mitochondrial membrane is a fundamental cellular process. This exchange is facilitated by the adenine nucleotide translocase (ANT), the structure and function of which is critically dependent on the signature phospholipid of mitochondria, cardiolipin (CL). Here we employ multiscale molecular dynamics simulations to investigate CL interactions within a membrane environment. Using simulations at both coarse-grained (CG) and atomistic (AT) resolutions, we identify three CL binding sites on the translocase, in agreement with those seen in crystal structures and inferred from NMR measurements. Characterisation of the free energy landscape for lateral lipid interaction via potential of mean force (PMF) calculations demonstrates the strength of interaction compared to binding sites on other mitochondrial membrane proteins, as well as their selectivity for CL over other phospholipids. Extending the analysis to the other members of the family, yeast Aac2p and mouse uncoupling protein 2 (UCP2), suggests a degree of conservation. Simulation of large patches of model mitochondrial membrane containing multiple copies of the translocase shows that CL interactions persist in the presence of protein-protein interactions, and suggests CL may mediate interactions between translocases. This study provides a key example of how computational microscopy may be used to shed light on regulatory lipidprotein interactions.

Authors: Sansom, M; Hedger, G; Rouse, S; Domański, J; Chavent, M

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: Biochemistry
• Volume: 55
• Issue: 45
• Pages: 6238–6249
• Publication date: 2016-10-01
• Acceptance date: 2016-10-27
• DOI: 10.1021/acs.biochem.6b00751
• ISSN: 1520-4995, 0006-2960