A Roadmap of Responses to Asymmetry Stress in Lipid Membranes

The selective insertion of membrane-impermeant amphiphiles such as detergents, (lipo)peptides, drugs, etc. into the cis leaflet of a membrane causes an imbalance between the intrinsic areas of the cis and trans leaflet, referred to as asymmetry stress or differential stress. The literature provides individual mechanisms of how membranes respond to such stress, which are relevant to membrane remodeling processes and leakage phenomena. By studying vesicle budding, membrane leakage, and isothermal titration calorimetry of liposomes interacting with digitonin, alkyl maltosides, miltefosine, and octyl glucoside, we developed a roadmap linking the stress-response mechanisms to each other. Initially, lateral compression or stretching of the leaflets accommodates a minor asymmetry stress. Then, either molecules flip to the trans leaflet or the membrane bends to form buds. Fast flip leads to the classic three-stage model. Budding proceeds up to its limit at 20-40% of the lipid. Beyond, insertion of further detergent is opposed by the pressure in the overpopulated leaflet. This "staying out" state can persist over hours or days and up to high detergent concentrations before detergent micelles induce "micellar solubilization". Alternatively, the stress can be reduced by a transient failure of the membrane, allowing for "cracking in" of molecules, transferring them to the trans side.