UCLA

Antimicrobial peptides (AMPs) preferentially permeate prokaryotic membranes via electrostatic binding and membrane remodeling. Such action is drastically suppressed by high salt due to increased electrostatic screening, thus it is puzzling how marine AMPs can possibly work. We examine as a model system, piscidin-1, a histidine-rich marine AMP, and show that ion-histidine interactions play unanticipated roles in membrane remodeling at high salt: Histidines can simultaneously hydrogen-bond to a phosphate and coordinate with an alkali metal ion to neutralize phosphate charge, thereby facilitating multidentate bonds to lipid headgroups in order to generate saddle-splay curvature, a prerequisite to pore formation. A comparison among Na⁺ , K⁺ , and Cs⁺ indicates that histidine-mediated salt tolerance is ion specific. We conclude that histidine plays a unique role in enabling protein/peptide-membrane interactions that occur in marine or other high-salt environment.