Molecular Dynamics Analysis of Cardiolipin and Monolysocardiolipin on Bilayer Properties

Abstract

The mitochondrial lipid cardiolipin (CL) contributes to the spatial protein organization and morphological character of the inner mitochondrial membrane. Monolysocardiolipin (MLCL), an intermediate species in the CL remodeling pathway, is enriched in the multisystem disease Barth syndrome. Despite the medical relevance of MLCL, a detailed molecular description that elucidates the structural and dynamic differences between CL and MLCL has not been conducted. To this end, we performed comparative atomistic molecular dynamics studies on bilayers consisting of pure CL or MLCL to elucidate similarities and differences in their molecular and bulk bilayer properties. We describe differential headgroup dynamics and hydrogen bonding patterns between the CL variants and show an increased cohesiveness of MLCL's solvent interfacial region, which may have implications for protein interactions. Finally, using the coarse-grained Martini model, we show that substitution of MLCL for CL in bilayers mimicking mitochondrial composition induces drastic differences in bilayer mechanical properties and curvature-dependent partitioning behavior. Together, the results of this work reveal differences between CL and MLCL at the molecular and mesoscopic levels that may underpin the pathomechanisms of defects in cardiolipin remodeling.

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).…”

Curvature sensing by cardiolipin in simulated buckled membranes

“…18,23,[44][45][46] Curved membrane surfaces can be generated by simulating spheres 47,48 or cylinders, 49 but require equilibration of lipids and solute in different leaflets and compartments, which is only feasible for strongly coarsegrained membrane models. In this work, we use simulated membrane buckling [50][51][52][53][54][55][56][57][58][59][60] and develop an elastic theory to overcome these difficulties. Our buckling method 59 is based on a reaction coordinate (the arc-length) along the membrane profile, which presents a continuous range of curvatures in a single simulation, and is amenable for comparison to elastic membrane theories.…”

“…1a) consists of two equivalently deformed monolayers, which due to periodic boundary conditions does not divide the solutes into multiple closed compartments. Thus, the distributions of various species along the buckled membrane reflect their respective curvature preferences, 53,54,[56][57][58][59][60] and equilibration is limited only by in-plane lipid diffusion. We use the coarse-grained Martini model [61][62][63] (Fig.…”

Molecular Mechanism of Action of Mitochondrial Therapeutic SS-31 (Elamipretide): Membrane Interactions and Effects on Surface Electrostatics

“…S14). Due to its conical molecular geometry, CL can cause localized exposure of acyl chains to the aqueous interface (27). Intercalation of SS-31 aromatic chains into these pockets could fill such interfacial "voids" (packing defects), which could in turn have implications for bilayer properties such as mechanostability and elasticity.…”