Polymorphic Phase Behavior of Cardiolipin Derivatives Studied by Coarse-Grained Molecular Dynamics

Abstract

Cardiolipin (CL) is a negatively charged four acyl chain lipid, associated with energy production in bacterial and mitochondrial membranes. Due to the shape of CL, negative curvatures of aggregates are favorable if the charges in the head group can be reduced. The phase polymorphism of CL, and of associated derivatives with 2, 3, 4, or 5 chains, has been determined previously and offers a model system in which micellar, lamellar, and inverse hexagonal phases can be observed. We present an extension to a previously established coarse-grained molecular dynamics model with the aim of reproducing the different CL phases with two adjustable parameters: the number of acyl chains and the effective head group charge. With molecular dynamics simulations of large lipid systems, we observed transitions between different phases on the nanosecond to microsecond time scale. Charge screening by high salt or low pH was successfully modeled by a reduction of phosphate charge, which led to the adoption of aggregates with more negative curvature. Although specific ion binding at the interface and other atomistic details are sacrificed in the coarse-grained model, we found that it captures general phase features over a large range of aggregate geometries.

Dynamic simulation of cardiolipin remodeling: greasing the wheels for an interpretative approach to lipidomics

“…diverse molecular species of cardiolipin have stimulated the investigation of numerous analytical and mathematical approaches to determine the importance of cardiolipin in biological function. Coarse-grained molecular dynamics, thermodynamics and thermal response, atomic force microscopy, and atomic-scale simulations have all been used to characterize structural orientation and interaction of cardiolipin in membrane dynamics (55)(56)(57)(58)(59)(60). More recently, mathematical models using linear algebraic representation have been used to explain the acyl selectivity of cardiolipin remodeling based on free energies ( 61 ).…”

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

“…Mitochondria are comprised of a unique double bilayer membrane structure that facilitates the compartmentalization of multiple processes to effi ciently integrate mitochondrial function with cellular energy needs ( 11,14,15 ). A prominent lipid regulator of mitochondrial inner membrane surface charge, molecular dynamics, and membrane curvature is cardiolipin, which contains a unique tetra-acyl structure ( 12,15,16 ). Cardiolipin is a doubly charged mitochondrial phospholipid comprised of two phosphates, three glycerol groups, and four acyl chains (17)(18)(19).…”

Endophilin B1/Bif-1 Stimulates BAX Activation Independently from Its Capacity to Produce Large Scale Membrane Morphological Rearrangements

“…Specifically, we probed for the impact of CL replacement by (i) another anionic lipid (PI) while keeping the net charge of the vesicle equal to that existing in CL-containing MOMlike LUV, (ii) mirCL, which unlike CL, tends to segregate into a distinct phase when combined with unsaturated lipids (40) (supplemental Fig. 4), and (iii) derivatives of CL, which do not share with the parent lipid the potential to adopt a negatively curved nonlamellar disposition (MCL, DCL) (41,42). Replacement of CL with PI, mirCL, or a MCL/ DCL mixture did not change substantially the ability of Bif-1 1-252 to induce intervesicular lipid mixing or to increase liposome size (Table 3).…”