Cholesterol-induced selectivity has been observed in cyclic peptides such as Lugdunin [100], S-thanatin . These peptides exhibit widely varying physicochemical properties: Lugdunin is lipophilic and neutral, Gramicidin S is amphipathic, and S-thanatin is polar and highly cationic. Also their pore-forming mechanisms differ significantly: Lugdunin forms tubes [100], Gramicidin S forms cation-specific channels after inducing membrane demixing and thinning , and S-thanatin destabilizes LPS by displacing divalent cations . The diversity in structure and function among these peptides makes the identification of a unifying principle for their cholesterol-induced selectivity challenging. However, the lipid-condensing effect of cholesterol is a common explanation, as cyclic AMPs often show shallower membrane penetration in cholesterol-rich environments . The cyclic structure also enables tighter control of conformational space, facilitating targeted modifications to enhance selectivity and reduce hemolysis, as demonstrated with Gramicidin S derivatives . Molecular dynamics simulations, paired with experimental methods, offer valuable insights into the cholesterol-induced selectivity of certain AMPs and the promiscuous behavior of others, such as Melittin . The study of cholesterol-containing membranes is essential because the differential insertion of AMPs into bacterial versus RBC membranes is influenced by the physical properties of the membrane . Cholesterol can overshadow electrostatic interactions by protecting even anionic bilayers, typical targets of cationic peptides, from antimicrobial activity . Therefore, examining peptide interactions solely with zwitterionic or anionic membrane models fails to capture the complexity underlying peptide selectivity. Realistic membrane models are crucial to account for eukaryotic membrane properties. For instance, the low bending modulus of RBC membranes (4 6k B T ) compared to 10k B T for a POPC:Cholesterol model membrane (ration 6:4) illustrates that incorporating cholesterol is a starting point but insufficient to replicate RBC properties.