Quantum chemical modeling of the cardiolipin headgroup

Cardiolipin is a key lipid component in many biological membranes. Proton conduction and proton-lipid interactions on the membrane surface are thought to be central to mitochondrial energy production. However, details on the cardiolipin headgroup structure are lacking and the protonation state of this lipid at physiological pH is not fully established. Here we present ab initio DFT calculations of the cardiolipin (CL) headgroup and its 2'-deoxy derivative (dCL), with the aim of establishing a connection between structure and acid-base equilibrium in CL. Furthermore, we investigate the effects of solvation on the molecular conformations. In our model, both CL and dCL showed a significant gap between the two pK(a) values, with pK(a2) above the physiological range, and intramolecular hydrogen bonds were found to play a central role in the conformations of both molecules. This behavior was also observed experimentally in CL. Structures derived from the DFT calculations were compared with those obtained experimentally, collected for CL in the Protein Data Bank, and conformations from previous as well as new molecular dynamics simulations of cardiolipin bilayers. Transition states for proton transfer in CL were investigated, and we estimate that protons can exchange between phosphate groups with an approximate 4-5 kcal/mol barrier. Computed NMR and IR spectral properties were found to be in reasonable agreement with experimental results available in the literature.