Modulation of the Interaction Between Detergent Micelles and Model Peptide Antibiotics by Varying the Peptide Charge Distribution

Abstract

With rising disease rates and decreasing effectiveness of conventional antibiotics, there is an immediate need for new antibiotics. One promising solution is through cationic antimicrobial peptides, which act by perturbing bacterial membranes. We are investigating model peptide antibiotics composed primarily of the hydrophobic dialkylated amino acid Aib (α-aminoisobutyric acid), which imparts a strong 310-helical bias due to steric hindrance at the α-carbon. Cationic lysine residues were placed in adjacent locations in the center of the helix (KK45) or one full turn apart (KK36). Micelles of dodecylphosphocholine (DPC) or sodium dodecyl sulfate (SDS) were used as zwitterionic or anionic membrane models, respectively. The interaction of model peptides with micelles can provide valuable information about the role of helical structure and peptide charge distribution on peptide-membrane interactions. Here we present thermodynamic and spectroscopic data characterizing the peptide-micelle interactions. Binding enthalpies for the interactions of KK36 and KK45 with DPC and SDS micelles were measured using isothermal titration calorimetry (ITC). Preliminary data suggests that binding to SDS micelles is exothermic, while binding to DPC micelles is endothermic. In both cases, KK45 has a more favorable binding enthalpy than KK36. Measurements of longitudinal relaxation times (T1) in the absence and presence of a gadolinium line broadening reagent indicate that KK45 is more buried than KK36 in SDS micelles, and that both peptides are more buried in SDS micelles than in DPC micelles. These results suggest that the enthalpy of binding is dominated by hydrophobic interactions between the Aib sidechains and the detergent molecules. These interactions are enhanced in KK45, possibly because the charges are more localized to the center of the helix.