Structural Determinants of the Energetic Barrier of Phospholipid Flip-Flop

Martini 3 simulations across 700+ membrane–lipid combinations show flip-flop free-energy barriers rise with tighter tail packing and depend strongly on headgroup and tail unsaturation.

• Why it matters: Experiments are few and contradictory, and prior simulations covered only a small lipidome, leaving how lipid chemistry and membrane environment jointly shape the energetic barrier unclear.
• What they did: The study calculates Martini 3 flip-flop barriers for a single-component panel (five headgroups, three linkages, 35 tail families) plus mixed bilayers, then fits a Bayesian model using chemical descriptors and local membrane structure.
• The result: The Bayesian model predicts withheld lipid families and membranes with cross-validated errors of 2.8 and 3.8 kJ/mol, matching vesicle trends qualitatively while Martini 3 underestimates lipid differences and overstates cholesterol effects.