Mitochondrial Proteins and Molecular Interaction with Cardiolipin at Atomistic Level

Abstract

Functional coupling between mitochondrial creatine kinase (MtCK) and adenine nucleotide translocase (ANT) can play an important role in determining energy transfer pathways in the cell. MtCK, which is an octameric enzyme, catalyzes the conversion of creatine (Cr) and consumes adenosine triphosphate (ATP) to create phosphocreatine (PCr) and adenosine diphosphate (ADP). Mitochondrial CK is located partly in contact sites of outer and inner mitochondrial membranes and partly in the cristae region, but always firmly attached to the inner membrane and in the vicinity of transmembrane ANTs. It is shown that MtCK binds electrostatically to the negatively charged cardiolipins (CL) of the inner membrane. CL is a kind of diphosphatidylglycerol lipid and is found almost exclusively in the inner mitochondrial membrane where it is essential for keeping spatially close and functional CK, ANT and other respiratory complexes. The formation of contact sites of CK-ANT by CL patches is a dynamic process and important to understand at atomistic level, which is the main goal of this work.The molecular dynamics simulation technique is used to study the atomistic details of the functional role of CL close to mitochondrial CK and ANT complexes. The thermodynamics-based coarse-grained force-field, called MARTINI (version 2.0), has been used together with the GROMACS molecular dynamics package (version 4.5.4) for a model of a patch of the mitochondrial inner membrane containing several transmembrane ANTs, and a single CK above the membrane. The membrane model consists of three major type of lipids ­ phosphatidylcholine, phosphatidylethanolamine and cardiolipin in roughly 2:1:1 molar ratio.