Thermotropic and barotropic phase behavior of phospholipid bilayers: A thermodynamic phase-diagram perspective incorporating modular lipid architecture

Understanding how lipid bilayer phase behavior responds to temperature and pressure is essential for elucidating membrane stability and adaptability under diverse environmental conditions. In this review, thermotropic and barotropic phase behavior of hydrated phospholipid bilayers is systematically organized using temperature ( T )–pressure ( p ) phase diagrams as a central framework. After outlining fundamental bilayer phase states and transitions using dipalmitoylphosphatidylcholine as a reference system, general features and thermodynamic interpretation of T – p phase diagrams are summarized to provide a unified basis for comparison. The main focus of this review is a modular structural analysis of phospholipid molecules, in which bilayer phase behavior is discussed in terms of three intrinsic molecular modules: the hydrophobic chain region (C module), the linkage connecting hydrophobic chains to the glycerol backbone (L module), and the polar head group (H module). Variations in these modules reshape T – p phase diagrams by altering intermolecular interactions within the bilayer core, backbone region, and membrane interface. Phase-boundary positions are highly sensitive to molecular structure, whereas d T /d p values primarily reflect the nature of the transition and, in specific cases, interfacial conditions such as head-group charge and salt concentration. Ligand effects, including solvent substitution, membrane-active molecules, and cholesterol, are discussed as extrinsic modifiers that regulate bilayer phase behavior by tuning thermodynamic contributions without altering transition mechanisms. Finally, the coexistence of structural diversity and conserved modular architecture in phospholipids is highlighted, and future perspectives based on chemically designed lipids with modified modular arrangements are discussed within the emerging framework of chemical lipidology. • T – p phase diagrams unify thermotropic and barotropic bilayer phase behavior. • Modular lipid architecture links molecular structure to phase-diagram topology. • Pressure reveals hidden gel polymorphism and interdigitated phase stability. • d T /d p slopes reveal transition mechanisms and interfacial contributions. • Ligands and cholesterol tune bilayer phases without changing core mechanisms.