Lateral heterogeneity of a cell membrane,including the formation of lipid raft-like clusters and the inter-leaflet cou-pling of specific phase domains,is crucial for cellular functions such as membrane trafficking and transmembrane signaling.However,the wide diversity in lipid species and the consequent complexity in lipid-lipid interplays hinder our understand-ing of the underlying mechanism.In this work,with coarse-grained molecular dynamics simulations,the effect of lipid tail structures on the phase behavior of a model ternary lipid membrane was systematically explored.A serial of 27 lipid membrane systems consisting of saturated,unsaturated lipids,and cholesterol(Chol)molecules,at a fixed molar ratio of 4:4:2 while varying in lipid structures including tail length,unsaturation degree,and/or position of unsaturated atoms,were constructed.These structural factors were found to exert sophisticated influences on packing states of the constituent molecules,especially Chol,in a bilayer,and modulate the complicated entropy-enthalpy competition of the membrane sys-tem accordingly.Specifically,an appropriate difference in effective tail length and distinct feature of the tail ends between the saturated and unsaturated lipid compositions promised an enhanced phase separation of the membrane into the Chol-rich Lo and Chol-poor Ld phase domains,with a full inter-leaflet coupling of each domain.Our results provide insights into the lipid organizations and segregations of the cellular plasma membrane.