Cardiolipin Models for Molecular Simulations of Bacterial and Mitochondrial Membranes

Abstract

Present in bacterial and mitochondrial membranes, cardiolipins have a unique dimeric structure, which carries up to two charges (i.e., one per phosphate group) and, under physiological conditions, can be unprotonated or singly protonated. Exhaustive models and characterization of cardiolipins are to date scarce; therefore we propose an ab initio parametrization of cardiolipin species for molecular simulation consistent with commonly used force fields. Molecular dynamics simulations using these models indicate a protonation dependent lipid packing. A peculiar interaction with solvating mono- and divalent cations is also observed. The proposed models will contribute to the study of the assembly of more realistic bacterial and mitochondrial membranes and the investigation of the role of cardiolipins for the biophysical and biochemical properties of membranes and membrane-embedded proteins.

Cardiolipin-Dependent Properties of Model Mitochondrial Membranes from Molecular Dynamics Simulations

“…Our simulation results are reported in Table 7 In general, the diffusion coefficients for POPC and DOPE match reasonable well with those expected from phospholipids in the liquid state (∼ 3 − 11 × 10 −8 cm 2 /s) (125). The values for CL compare favorably to previously published diffusion coefficients for tetramyristol CL (∼ 5 × 10 −8 cm 2 /s) (126) and tetraoleoyl CL (∼ 4 × 10 −8 cm 2 /s) (127) in liquid phase unary CL bilayers. The trends in D l values with CL content are correlated with changes in the partial areas per lipid acyl chain, consistent with the correlation between the lateral lipid packing density and lipid diffusion reported by Javanainen et al (92).…”

Cardiolipin Structure and Oxidation Are Affected by Ca2+ at the Interface of Lipid Bilayers

“…Most studies are consistent with CL as being fully deprotonated at physiological pH and rest on a single pK a value for both phosphate groups of the lipid (Blume et al, 1988;Lewis et al, 1994;Lewis and McElhaney, 2000;Kooijman et al, 2017). In the minority, some studies have demonstrated two widely separated pK a values (Hübner et al, 1991;Kates et al, 1993;Gorbenko et al, 2006;Hielscher et al, 2009) and include the theoretical study of Dahlberg et al (2010) and Lemmin et al (2013). It is not the main objective of the present study to approach the question of cardiolipin pK a values.…”

“…The authors estimated that protons could exchange between phosphate groups with an energy barrier of ∼4-5 kcal/mol. Lemmin et al stated that indepth models and characterization of cardiolipins are to date rare and proposed an ab initio parametrization of cardiolipin species for molecular simulation and concluded that the cardiolipin protonation influences the lipid packing (Lemmin et al, 2013). The authors also investigated the interactions with Na + and Mg 2+ but not Ca 2+ .…”

Cardiolipin containing liposomes are fully ionized at physiological pH. An FT-IR study of phosphate group ionization

“…These authors claim two rather distinguishable protonation processes, one with pK = 2.8 and a second one varying between 7.5 and 9.5 [8]. This result is corroborated indirectly by computational studies of Lemmin et al who claimed based on the results of molecular dynamics (MD) simulations that CL with a mixed protonation state can explain multiple biophysical properties of CL-rich membrane portions [9]. Results from ab initio calculations for the CL head groups suggest a stabilization by a bicyclic resonance structure formed by the two phosphate groups and adjacent hydroxyl groups.…”