The mitochondrial lipid cardiolipin (CL) contributes to the spatial protein organization and morphological character of the inner mitochondrial membrane. CL has been suggested to self-organize into lipid domains due to its inverted conical molecular geometry, though the driving forces for this organization are not fully understood. In this work, we use coarse-grained (CG) molecular dynamics (MD) simulations to study the mechanical properties and lipid dynamics in heterogeneous bilayers both with and without CL as a function of membrane curvature. We find that incorporation of CL increases bilayer deformability and that CL becomes highly enriched in regions of high negative curvature. We further show that another mitochondrial inverted conical lipid, phosphatidylethanolamine (PE), does not partition or increase the deformability of the membrane in a significant manner, and therefore the unique properties of CL cannot be explained purely from lipid packing theory.<br/>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 increased cohesiveness of MLCL’s solvent interfacial region, which may have implications for protein interactions. Finally, using CG simulations, 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.<br/>

Curvature based lipid segregation and stability modulation in bilayers containing cardiolipin and monolysocardiolipin

255th National Meeting (2018)

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