Charge-based interactions of antimicrobial peptides and general drugs with lipid bilayers

Membrane-active agents (MAAs), such as antimicrobial peptides (AMPs) and chemotherapy drugs (CDs), induce ion pores/channels inside lipid bilayer membrane, as confirmed by standard electrophysiology experiments. A novel experimental method is described which detects agents directly at the membrane as confirmed for MAAs, CDs and aptamers. MAAs exhibit characteristic ‘charge based’ interactions with lipids. Electrostatic (ES) and van der Waals (vdW) contributions to the interaction energies have been estimated using molecular dynamics (MD) simulations. These results are consistent with the screened Coulomb interaction predictions recently developed for lipid bilayer binding of integral AMP channels. Energy- and distance-dependence of MAA-lipid interactions from MD simulations are represented by universal probability functions. A generalized model of MAA-lipid interactions is developed based on the charge and geometrical profiles of the participating lipids and AMPs. The corresponding driving force correlates directly with the stability of MAA-lipid structures as observed in electrophysiology experiments. We conclude that MAAs and similar agents that target lipid membranes exhibit physiological effects mainly due to ES and vdW interactions determined by their charge profiles. [Display omitted] •Novel direct detection method detects membrane-active agents directly at membrane.•Agents interact with bilayers due to van der Waals and electrostatic interactions.•Assembly of antimicrobial peptides and general drugs in lipid bilayers.•The interaction energy trends are represented by universal probability functions.•Screened Coulomb interactions inclusion is a major advancement in membrane physics. Significance: We demonstrate experimentally and computationally that membrane-active agents interact with lipid bilayers due to compound- and phospholipid-specific van der Waals and electrostatic interactions. By doing so they regulate membrane properties. The inclusion of screened Coulomb interactions is a significant advance in membrane biophysics.