Spectrin,the principal protein of the cytoskeleton of erythrocyte,plays a crucial role in the stability and flexibility of the plasma membrane of erythrocyte.In this work,we investigate the interactions between spectrins and phase-separated lipid bilayers using coarse-grained molecular dynamics simulation.We focus on the preference of spectrins with differ-ent lipids,the effects of the anionic lipids and the residue mutation on the interactions between spectrins and the lipid bilayers.The results indicate that spectrins prefer to contact with phosphatidylethanolamine (PE) lipids rather than with phosphatidylcholine (PC) lipids,and tend to contact with the liquid-disordered (Ld) domains enriched in unsaturated PE.Additionally,the anionic lipids,which show specific interaction with the positively charged or polar amino acids on the surface of the spectrins,can enhance the attraction between the spectrins and lipid domains.The mutation leads to the decrease of the structural stability of spectrins and increases the curvature of the lipid bilayer.This work provides some theoretical insights into understanding the erythrocyte structure and the mechanism of some blood diseases.