The paper by William C. Wimley discusses the mechanisms of action of antimicrobial peptides (AMPs) and proposes an "interfacial activity model" to bridge the gap between synthetic vesicle experiments and microbial experiments. AMPs, which are cationic and amphipathic, have broad-spectrum antimicrobial activity through membrane permeabilization. The interfacial activity model suggests that AMPs perturb the lipid-water interface of membranes, altering lipid packing and organization without necessarily forming transmembrane pores. This model is based on the observation that AMPs bind to membranes and partition into the interfacial region, driving local rearrangements in lipid packing. The model is supported by molecular dynamics simulations and experimental data, and it provides a framework for understanding and engineering novel AMPs. The paper also highlights the importance of interfacial activity in predicting AMP activity and suggests that it may be a useful surrogate for broad-spectrum antimicrobial activity.The paper by William C. Wimley discusses the mechanisms of action of antimicrobial peptides (AMPs) and proposes an "interfacial activity model" to bridge the gap between synthetic vesicle experiments and microbial experiments. AMPs, which are cationic and amphipathic, have broad-spectrum antimicrobial activity through membrane permeabilization. The interfacial activity model suggests that AMPs perturb the lipid-water interface of membranes, altering lipid packing and organization without necessarily forming transmembrane pores. This model is based on the observation that AMPs bind to membranes and partition into the interfacial region, driving local rearrangements in lipid packing. The model is supported by molecular dynamics simulations and experimental data, and it provides a framework for understanding and engineering novel AMPs. The paper also highlights the importance of interfacial activity in predicting AMP activity and suggests that it may be a useful surrogate for broad-spectrum antimicrobial activity.