Alkylphospholipids relax membrane curvature by geometric compensation

Miltefosine, a member of the alkylphospholipids (APLs) family, is an amphiphilic drug previously shown to have the capacity to relax curved membrane structures. In the present work, we explored if this capacity is given by molecular geometry compensation. Due to their geometric similarity, we extended our study to other members of the APL family, edelfosine and perifosine. Here, we report that curved lipid structures are altered by the incorporation of APLs, which modulate the membrane spontaneous curvature by stabilising planar membranes. Phospholipid membranes forming HII phase are destabilised, favouring Lα lamellas when APLs are incorporated symmetrically. Furthermore, externally added APLs monomers are rapidly incorporated into phospholipid membranes and its asymmetric enrichment results in lowering the curvature stress promoting retraction of highly curved inner nanotube structures in giant unilamellar vesicles. Our results confirmed a geometric compensation of APLs with Type-II lipids, which is more pronounced for miltefosine and edelfosine than in the case of perifosine. Additionally, we developed a simple and affordable approach for the analysis of heterogeneous model membranes based on the quantitative method of LAURDAN spectral phasors.