(578g) A Statistical Mechanical Model of Antimicrobial Peptide Action: Peptide Aggregation, Membrane Adsorption and Membrane Insertion Equilibria

Protegrin-1 (PG1) is a naturally-occurring peptide with strong antimicrobial properties and a promising outlook for therapeutic antibiotic use. Previous experimental studies have identified several key steps in the action of PG1, including peptide aggregation, adsorption to the surface of the cell membrane, and insertion into the hydrophobic membrane core. We present herein a quantitative model based on statistical mechanical considerations of these processes, as well as the potentials of mean force for peptide dimerization, adsorption and insertion, as computed from all-atom molecular dynamics simulations. We account for the effects of surface crowding and nonideal adsorption using the scaled particle theory (SPT) approach, and also account for the effects of membrane area expansion due to the insertion of peptides into the membrane core. The changes in the electrostatic potential at the surface and its effects on adsorption equilibria are treated using classical Gouy-Chapman theory. Our model provides the surface densities of adsorbed and inserted monomeric and dimeric peptides as a function of the total bulk solution concentration. Based on these results, we can compute the membrane fractional area expansion, which shows surprisingly good quantitative agreement with the corresponding results of Langmuir trough monolayer expansion experiments. From our model, we are able to conclude that the dominant state for protegrin peptides interacting with a membrane-like environment is the dimer form inserted in the membrane core. In addition to energetic driving forces, we find that surface crowding beyond certain values can act as a driving force for peptide insertion, which yields a maximum in the adsorption isotherm of any surface-bound species, and suggests a novel cooperative element in the action of this peptide. The modeling tools that we present herein are widely applicable to other antimicrobial peptide systems, and indeed any other protein-membrane systems.