Event Title

Designing Better Antibiotics: Modeling the Interaction Between Model Antimicrobial Peptides and Detergent Micelles

Mentor 1

Dr. Adrienne Loh

Location

Union Wisconsin Room

Start Date

24-4-2015 10:30 AM

End Date

24-4-2015 11:45 AM

Description

With rising disease rates and decreasing effectiveness of conventional antibiotics, there is an immediate need for new antibiotics. One promising solution is through positively charged antimicrobial peptides, which act by perturbing bacterial membranes. We are investigating model peptide antibiotics composed primarily of the hydrophobic, branched amino acid Aib (α-aminoisobutyric acid), which is often found in helical peptides due to steric hindrance at the α-carbon. Positively charged lysine residues were placed in adjacent locations in the center of the helix (KK45) or one full turn apart (KK36). Micelles of the detergent molecules dodecylphosphocholine (DPC) or sodium dodecyl sulfate (SDS) were used as neutral or negatively charged 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). It was determined that binding to SDS micelles is favorable, or exothermic, while binding to DPC micelles is unfavorable, or endothermic, indicating that charge interactions dominate the binding enthalpies. In both cases, KK45 has a more favorable binding enthalpy than KK36, suggesting that charge distribution (and not just total charge) is also important. NMR measurements that indicate which regions of the peptides are buried in the micelle 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 peptide-micelle interactions are enhanced with KK45, due to greater charge density and/or a more favorable helical structure.

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Apr 24th, 10:30 AM Apr 24th, 11:45 AM

Designing Better Antibiotics: Modeling the Interaction Between Model Antimicrobial Peptides and Detergent Micelles

Union Wisconsin Room

With rising disease rates and decreasing effectiveness of conventional antibiotics, there is an immediate need for new antibiotics. One promising solution is through positively charged antimicrobial peptides, which act by perturbing bacterial membranes. We are investigating model peptide antibiotics composed primarily of the hydrophobic, branched amino acid Aib (α-aminoisobutyric acid), which is often found in helical peptides due to steric hindrance at the α-carbon. Positively charged lysine residues were placed in adjacent locations in the center of the helix (KK45) or one full turn apart (KK36). Micelles of the detergent molecules dodecylphosphocholine (DPC) or sodium dodecyl sulfate (SDS) were used as neutral or negatively charged 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). It was determined that binding to SDS micelles is favorable, or exothermic, while binding to DPC micelles is unfavorable, or endothermic, indicating that charge interactions dominate the binding enthalpies. In both cases, KK45 has a more favorable binding enthalpy than KK36, suggesting that charge distribution (and not just total charge) is also important. NMR measurements that indicate which regions of the peptides are buried in the micelle 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 peptide-micelle interactions are enhanced with KK45, due to greater charge density and/or a more favorable helical structure.